Factor Xa inhibitors

ABSTRACT

The present invention is directed to compounds of formula (I) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to intermediates used in making such compounds, pharmaceutical compositions containing such a compound, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119 (e) of U.S.Provisional Application Ser. No. 60/883,667, filed Jan. 5, 2007, andU.S. Provisional Application Ser. No. 60/797,954, filed May 5, 2006,both of which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to substituted imidazole compounds which actas inhibitors of Factor Xa. This invention is also directed topharmaceutical compositions containing the substituted imidazolecompounds and methods of using the compounds or compositions to treat acondition characterized by undesired thrombosis. The invention is alsodirected to methods of making the compounds described herein.

2. State of the Art

Hemostasis, the control of bleeding, occurs by surgical means, or by thephysiological properties of vasoconstriction and coagulation. Thisinvention is particularly concerned with blood coagulation and ways inwhich it assists in maintaining the integrity of mammalian circulationafter injury, inflammation, disease, congenital defect, dysfunction orother disruption. Although platelets and blood coagulation are bothinvolved in restoring hemostasis and in thrombotic diseases, certaincomponents of the coagulation cascade are primarily responsible for theamplification and acceleration of the processes involved in plateletaggregation and fibrin deposition which are major events in thrombosisand hemostasis.

Clot formation involves the conversion of fibrinogen to fibrin whichpolymerizes into a network to restore hemostasis after injury. A similarprocess results in occluded blood vessels in thrombotic diseases. Theconversion of fibrinogen to fibrin is catalyzed by thrombin, the endproduct of a series of reactions in the blood coagulation cascade.Thrombin is also a key player in activating platelets, therebycontributing to thrombosis under conditions of both arterial and venousblood flow. For these reasons, it has been postulated that efficientregulation of thrombin can lead to efficient regulation of thrombosis.Several classes of currently used anticoagulants directly or indirectlyaffect thrombin (i.e. unfractionated heparins, low-molecular weightheparins, heparin-like compounds, pentasaccharide and warfarin). Director indirect inhibition of thrombin activity has also been the focus of avariety of anticoagulants in clinical development (reviewed by Erikssonand Quinlan, Drugs 11: 1411-1429, 2006).

Prothrombin, the precursor for thrombin, is converted to the activeenzyme by factor Xa. Localized activation of tissue factor/factor VIIamediated factor Xa generation is amplified by the factor IXa/factorVIIIa complex and leads to prothrombinase assembly on activatedplatelets. Factor Xa, as a part of the prothrombinase complex, is thesole enzyme responsible for sustained thrombin formation in thevasculature. Factor Xa is a serine protease, the activated form of itsprecursor Factor X, and a member of the calcium ion binding, gammacarboxyglutamic acid (GLA)-containing, vitamin K dependent, bloodcoagulation factors. Unlike thrombin, which acts on a variety of proteinsubstrates including fibrinogen and the PAR receptors (Proteaseactivated receptors, Coughlin, J Thrombosis Haemostasis 3: 1800-1814,2005), factor Xa appears to have a single physiologic substrate, namelyprothrombin. Since one molecule of factor Xa may be able to generategreater than 1000 molecules of thrombin (Mann, et al., J. Thrombosis.Haemostasis 1: 1504-1514, 2003), direct inhibition of factor Xa as a wayof indirectly inhibiting the formation of thrombin may be an efficientanticoagulant strategy. This assertion is based on the key role ofprothrombinase in thrombin synthesis and on the fact that inhibition ofprothrombinase will have a pronounced effect on the overall plateletaggregation and clotting pathways.

Activated proteases such as factor VIIa, factor IXa or factor Xa havepoor proteolytic activity on their own. However, their assembly intocofactor-dependent, membrane-bound complexes significantly enhancestheir catalytic efficiencies. This effect is most dramatic for factorXa, where the efficiency is increased by a factor of 10⁵ (Mann, et al.,Blood 76(1):1-16, 1990). Due to the higher concentration of the zymogenspresent in blood (1.4 micromolar prothrombin versus 150 nanomolar factorX) and the kinetics of activation, a smaller amount of factor Xa thanthrombin needs to be inhibited to achieve an anticoagulant effect.Indirect proof of the hypothesis of superiority of factor Xa as atherapeutic target compared to thrombin can also be found in clinicaltrials for the prevention of deep vein thrombosis. Fondaparinux, anantithrombin III dependent factor Xa inhibitor, was proven to besuperior to enoxaparin (a low molecular weight heparin that inhibitsboth thrombin and factor Xa) in four trials of orthopedic surgery(Turpie, et al., Archives Internal Medicine 162(16): 1833-1840, 2002).Therefore, it has been suggested that compounds which selectivelyinhibit factor Xa may be useful as in vitro diagnostic agents, or fortherapeutic administration in certain thrombotic disorders, see e.g., WO94/13693.

Several Factor Xa inhibitors have been reported as polypeptides derivedfrom hematophagous organisms, as well as compounds which are not largepolypeptide-type inhibitors. Additional Factor Xa inhibitors includesmall molecule organic compounds, such as nitrogen containingheterocyclic compounds which have amidino substituent groups, whereintwo functional groups of the compounds can bind to Factor Xa at two ofits active sites. For example, WO 98/28269 describes pyrazole compoundshaving a terminal C(═NH)—NH₂ group; WO 97/21437 describes benzimidazolecompounds substituted by a basic radical which are connected to anaphthyl group via a straight or branched chain alkylene, —C(═O) or—S(═O)₂ bridging group; WO 99/10316 describes compounds having a4-phenyl-N-alkylamidino-piperidine and4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenylgroup via a carboxamidealkyleneamino bridge; and EP 798295 describescompounds having a 4-phenoxy-N-alkylamidino-piperidine group connectedto an amidinonaphthyl group via a substituted or unsubstitutedsulfonamide or carboxamide bridging group.

There exists a need for effective therapeutic agents for the regulationof hemostasis, and for the prevention and treatment of thrombusformation and other pathological processes in the vasculature induced bythrombin such as restenosis and inflammation. In particular, therecontinues to be a need for compounds which selectively inhibit factor Xaor its precursors. Compounds that have different combinations ofbridging groups and functional groups than compounds previouslydiscovered are needed, particularly compounds which selectively orpreferentially bind to Factor Xa. Compounds with a higher degree ofbinding to Factor Xa than to thrombin are desired, especially thosecompounds having good bioavailability and/or solubility.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds having thefollowing formula:

In formula (I), the symbol Z is selected from the group consisting of:

The symbol R¹ is selected from the group consisting of halogen, C₁₋₈alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl. The symbol R^(1a) is hydrogen orC₁₋₄ alkyl.

The symbol R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, C₁₋₄ alkyl, SR^(4a), S(O)R^(4a),S(O)₂R^(4a), COR^(4a), CO₂ R^(4a), CONR^(4a)R^(4b), CN, andS(O)₂NR^(4a)R^(4b).

The symbol R⁴ represents a moiety independently selected from the groupconsisting of hydrogen, halogen, OR^(4a), SR^(4a), S(O)R^(4a),S(O)₂R^(4a), NR^(4a)R^(4b), CO₂R^(4a),

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, amino, oxo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, hydroxy, C₁₋₈ alkoxy,heterocycloalkyl, heteroaryl, and heteroaryl-C₁₋₄ alkyl.

The symbols R^(4a) or R^(4b) are independently hydrogen or C₁₋₄ alkyl,optionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of halogen, hydroxyl, alkoxy,heterocyclyl, oxo, amino, and carboxyl. The subscript n is an integerfrom 0 to 2.

The symbol R⁵ is selected from the group consisting of:

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —NH—C(O)—C₁₋₈ alkyl, hydroxy,amino, oxo, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl, andheteroaryl-C₁₋₄ alkyl, with the proviso that when R⁵ is

then there cannot be an alkyl (or substituted alkyl) substituent in the5-position of the R⁵ ring.

Surprisingly, it has been found that the inclusion of the R⁵ ring grouphaving at least one exo bond (i.e., ═O, ═N—R, ═S) and being attachedthrough the nitrogen atom provides improved pharmacokinetic properties.

The symbol R⁶ is selected from the group consisting of hydrogen,halogen, and C₁₋₄ alkyl.

The symbol R⁷ is selected from the group consisting of hydrogen, C₁₋₄alkyl, cyano, optionally substituted phenyl, and C(O)R⁹ wherein R⁹ is C₁₋₄ alkyl or amino.

The symbol R⁸ is selected from the group consisting of hydrogen and C₁₋₄alkyl.

The wavy line indicates the point of attachment to the rest of themolecule.

The present invention also contemplates pharmaceutically acceptablesalts, esters, and prodrugs of the compounds of formula I.

The present invention further provides compounds in purified forms,chemical intermediates, pharmaceutical compositions and methods forpreventing or treating a condition in a mammal characterized byundesired thrombosis comprising the step of administering to the mammala therapeutically effective amount of a compound of the presentinvention. Such conditions include but are not limited to acute coronarysyndrome, myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, conditions requiring the fitting of prostheticdevices, and the like.

The present invention further provides methods for inhibiting thecoagulation of a blood sample comprising contacting the sample with acompound of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Shows mean plasma concentration-time profiles of compound 10 inmale Sprague-Dawley rats after 1 mg/kg intravenous (●) and 10 mg/kg oral(▪) administration (n=3/group). Plasma samples were measured usingLC/MS/MS.

FIG. 2. Mean plasma concentration-time profiles of compound 10 in malebeagle dogs after 1 mg/kg intravenous (●) and 5 mg/kg oral (▪)administration (n=3/group). Plasma samples were measured using LC/MS/MS.

FIG. 3. Shows mean plasma concentration-time profiles of compound 10 inmale rhesus monkeys after 1 mg/kg intravenous (●) and 5 mg/kg oral (▪)administration (n=3/group). Plasma samples were measured using LC/MS/MS.

DETAILED DESCRIPTION OF THE INVENTION 1. Abbreviations and Definitions

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group is one having one or more, preferably 1 to 3,double bonds. Similarly, the term “alkynyl” refers to an unsaturatedalkyl group having one or more, preferably 1 to 3, triple bonds.Examples of such unsaturated alkyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆ cycloalkyl) and being fully saturatedbetween ring vertices. The term “cycloalkenyl” refers to a cycloalkylgroup that has at least one point of alkenyl unsaturation between thering vertices. The term “cycloalkynyl” refers to a cycloalkyl group thathas at least one point of alkynyl unsaturation between the ringvertices. When “cycloalkyl” is used in combination with “alkyl,” as inC₃₋₅ cycloalkyl-alkyl, the cycloalkyl portion is meant to have thestated number of carbon atoms (e.g., from three to five carbon atoms),while the alkyl portion is an alkylene moiety having from one to threecarbon atoms (e.g., —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—).

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms.

Unless stated otherwise, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, and alkylene refer to both substituted andunsubstituted groups in which 1 or more, such as 1 to 5, hydrogen atomsis replaced by a substituent independently selected from the groupconsisting of ═O, ═S, acyl (—C(O)—R), acyloxy (—O—C(O)—R), alkoxy,alkoxyamino (—NH—O-alkyl), hydroxyamino (—NH—OH), amino, substitutedamino such as —NH₂ where one or more of the hydrogens may be optionallyreplaced by another suitable group, such as alkylamino and dialkylamino,or wherein the amino group may be a cyclic amine, aryl, heterocyclyl,azido (—N₃), carboxyl (—C(O)OH), alkoxycarbonyl (—C(O)—O-alkyl), amido(—C(O)-amino), cyano (—CN), cycloalkyl, cycloalkenyl, halogen, hydroxyl,nitro, sulfonylamino (—N(R)—S(O)₂—OR), aminosulfonyl (—S(O)₂-amino),sulfanyl (—S—R), sulfinyl (—S(O)—R), sulfonyl (—S(O)₂—R), and sulfonicacid (—S(O)₂—OH), wherein each R may independently be hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocycle.

The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom (—O-alkyl),an amino group, or a sulfur atom (—S-alkyl), respectively. Additionally,for dialkylamino groups (typically provided as —NR^(a)R^(b) or a variantthereof, where R^(a) and R^(b) are independently alkyl or substitutedalkyl), the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include a cyclic aminie having 3 to 6 carbon atoms andoptionally additional heteroatoms, such as O, S, and N, including butnot limited to piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl up to the maximumnumber of halogens permitted. For example, the term “C₁₋₈ haloalkyl” ismeant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “hydroxy” or “hydroxyl” refers to the group —OH.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, whichcan be a single ring or multiple rings (up to three rings) which arefused together or linked covalently. The term “heteroaryl” refers toaryl groups (or rings) that contain from one to five heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom or through a carbon atom and can contain 5to 10 carbon atoms. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. If not specifically stated, substituents foreach of the above noted aryl and heteroaryl ring systems are selectedfrom the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like).

The term “heterocycle” or “heterocyclyl” or “hetreocyclic” refers to asaturated or unsaturated non-aromatic cyclic group containing at leastone sulfur, nitrogen or oxygen heteroatom. Each heterocycle can beattached at any available ring carbon or heteroatom. Each heterocyclemay have one or more rings. When multiple rings are present, they can befused together or linked covalently. Each heterocycle must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 1-10 carbonatoms, 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. Morepreferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atomsand 0-1 oxygen atoms.

Non-limiting examples of heterocycle and heteroaryl groups includepyridine, pyridimidine, pyrazine, morpholin-3-one, piperazine-2-one,pyridine-2-one, piperidine, morpholine, piperazine, isoxazole,isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline,pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole, pyrazol-5-one, pyrrolidine-2,5-dione,imidazolidine-2,4-dione, pyrrolidine, pyrrole, furan, thiophene, and thelike.

The term “heterocycloalkyl” refers to the group alkylene-heterocycle,wherein both heterocycle and alkylene are as defined above.

The above terms (e.g., “aryl” and “heteroaryl”), in some embodiments,will include both substituted and unsubstituted forms of the indicatedradical. Preferred substituents for each type of radical are providedbelow. For brevity, the terms aryl and heteroaryl will refer tosubstituted or unsubstituted versions as provided below.

Substituents for the aryl, heteroaryl, and heterocycle groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the ring system; andwhere R′, R″ and R′″ are independently selected from hydrogen, C₁₋₈alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, unsubstituted aryland heteroaryl, (unsubstituted aryl)-C₁₋₄alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. This group of substituents is also used todescribe the substituents for optionally substituted phenyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

“Amino” refers to the group —NH₂ and unless otherwise specificied, alsorefers to “substituted amino.”

“Substituted amino” refers to the group —NR′R″ where R′ and R″ areindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, —SO₂-alkyl, —SO₂-alkenyl, —SO₂-cycloalkyl,—SO₂-cycloalkenyl, —SO₂-aryl, —SO₂-heteroaryl, and —SO₂-heterocyclic,and wherein R′ and R″ are optionally joined, together with the nitrogenbound thereto to form a heterocyclic or substituted heterocyclic group,provided that R′ and R″ are both not hydrogen, and wherein alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclic are as defined herein. When R′ is hydrogen and R″ is alkyl,the substituted amino group is sometimes referred to herein asalkylamino. When R′ and R″ are alkyl, the substituted amino group issometimes referred to herein as dialkylamino. When referring to amonosubstituted amino, it is meant that either R′ or R″ is hydrogen butnot both. When referring to a disubstituted amino, it is meant thatneither R′ nor R″ are hydrogen.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to—C(═O)—.

“Cyano” refers to the group —CN.

“Oxo” refers to the atom (═O) or (—O⁻).

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science,1977, 66, 1-19). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a ester form. For example, in the case of a carboxylic acid(—COOH) or alcohol group being present in the compounds of the presentinvention, pharmaceutically acceptable esters of carboxylic acidderivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acylderivatives of alcohols, such as acetate or maleate, can be employed.The invention includes those esters and acyl groups known in the art formodifying the solubility or hydrolysis characteristics for use assustained-release or prodrug formulations.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

2. Embodiments of the Invention

a. Compounds

In one aspect, the present invention provides compounds having thefollowing formula:

In formula (I), the symbol Z is selected from the group consisting of:

The symbol R¹ is selected from the group consisting of halogen, C₁₋₈alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl. The symbol R^(1a) is hydrogen orC₁₋₄ alkyl.

The symbol R² and R³ are independently selected from the groupconsisting of hydrogen, halogen, C₁₋₄ alkyl, SR^(4a), S(O)R^(4a),S(O)₂R^(4a), COR^(4a), CO₂R^(4a), CONR^(4a)R^(4b), CN, andS(O)₂NR^(4a)R^(4b).

The symbol R⁴ represents a moiety independently selected from the groupconsisting of hydrogen, halogen, OR^(4a), SR^(4a), S(O)R^(4a),S(O)₂R^(4a), NR^(4a)R^(4b), CO₂R^(4a),

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, amino, oxo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, hydroxy, C₁₋₈ alkoxy,heterocycloalkyl, heteroaryl, and heteroaryl-C₁₋₄ alkyl.

The symbols R^(4a) or R^(4b) are independently hydrogen or C₁₋₄ alkyl,optionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of halogen, hydroxyl, alkoxy,heterocyclyl, oxo, amino, and carboxyl.

The subscript n is an integer from 0 to 2.

The symbol R⁵ is selected from the group consisting of:

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —NH—C(O)—C₁₋₈ alkyl, hydroxy,amino, oxo, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl, andheteroaryl-C₁₋₄ alkyl, with the proviso that when R⁵ is

then there cannot be an alkyl (or substituted alkyl) substituent in the5-position of the R⁵ ring.

The structure shown above as:

includes both the cis and trans isomers, i.e.,

The symbol R⁶ is selected from the group consisting of hydrogen,halogen, and C₁₋₄ alkyl.

The symbol R⁷ is selected from the group consisting of hydrogen, C₁₋₄alkyl, cyano, optionally substituted phenyl, and C(O)R⁹ wherein R⁹ isC₁₋₄ alkyl or amino.

The symbol R⁸ is selected from the group consisting of hydrogen and C₁₋₄alkyl.

The wavy line indicates the point of attachment to the rest of themolecule. The present invention also contemplates pharmaceuticallyacceptable salts, esters, and prodrugs of the compounds of formula (I).

With the above formula, are a number of specific embodiments of theinvention. In one group of embodiments, R², R³ and R⁶ are hydrogen. Inone group of embodiments, R² is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, SR^(4a), S(O)R^(4a), S(O)₂R^(4a), COR^(4a),CO₂R^(4a), CONR^(4a)R^(4b), CN, and S(O)₂NR^(4a)R^(4b). In one group ofembodiments, R² is selected from the group consisting of hydrogen,methyl, —S-methyl, —S(O)-methyl, and —S(O)₂-methyl. In one group ofembodiments, R³ is hydrogen or methyl. In one group of embodiments, R⁶is hydrogen or fluoro. In one group of embodiments, R⁴ is selected fromthe group consisting of hydrogen, halogen, OR^(4a), S(O)R^(4a),S(O)₂R^(4a), NR^(4a)R^(4b)CO₂R^(4a),

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, amino, oxo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, hydroxy, C₁₋₈ alkoxy,heterocycloalkyl, heteroaryl, and heteroaryl-C₁₋₄ alkyl; and each R^(4a)or R^(4b) is independently hydrogen or C₁₋₄ alkyl, optionallysubstituted with hydroxyl, alkoxy, or heterocyclyl, and the wavy lineindicates the point of attachment to the rest of the molecule. Thesuperscript n is 0, 1, and 2.

In one embodiment, R⁴ is selected from the group consisting of hydrogen,hydroxyl, fluoro, S(O)CH₃, S(O)₂CH₃, NH(CH₂)₂OH, —C(O)₂CH₃,—O(CH₂)₂OCH₃, —OCH₂CH(OH)CH₂OH,

In another group of embodiments, R⁵ is

optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halogen, amino, C₁₋₈ alkyl, C₁₋₈haloalkyl, hydroxy, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl andheteroaryl-C₁₋₄ alkyl.

In another embodiment, the invention contemplates a compound having theformula:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, R⁵ is

optionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halogen, amino, C₁₋₈ alkyl, C₁₋₈haloalkyl, hydroxy, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl andheteroaryl-C₁₋₄ alkyl; and the subscript n is 0, 1, or 2.

In another embodiment, the invention contemplates compounds having theformulas:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, R⁵ is selected from the groupconsisting of

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, C₁₋₈ alkyl, —NH—C(O)—C₁₋₈ alkyl, C₁₋₈ haloalkyl, hydroxy,amino, oxo, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl andheteroaryl-C₁₋₄ alkyl and R⁸ is hydrogen or C₁₋₄ alkyl.

In another embodiment, the invention contemplates compounds having theformula selected from the group consisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In one group of embodiments, R⁵ is

wherein R⁷ is selected from the group consisting of hydrogen, C₁₋₄alkyl, cyano, optionally substituted phenyl, and C(O)R⁹. R⁹ is C₁₋₄alkyl or amino.

In those embodiments, the invention includes compounds selected from:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In one group of embodiments, Z is selected from the group consisting of:

and R¹ is halogen or C₂₋₈ alkynyl and R^(1a) is hydrogen or methyl.

In another group of embodiments, Z is:

In another embodiment, the invention contemplates compounds having theformula:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, Z is:

and R¹ is halogen or C₂₋₈ alkynyl.

In another group of embodiments, Z is:

where R¹ is halogen or C₂₋₈ alkynyl and R^(1a is) hydrogen or methyl.

The invention contemplates compounds having the formula:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, the compound has the following formula:

With reference to formula (II), R¹ is selected from the group consistingof halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; R² and R³ areindependently selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, SR^(4a), S(O)R^(4a), and S(O)₂R^(4a); and R⁴ is selectedfrom the group consisting of hydrogen, halogen, OR^(4a), SR^(4a),S(O)R^(4a), S(O)₂R^(4a), NR^(4a)R^(4b), CO₂R^(4a),

-   -   wherein each of these ring systems is optionally substituted        with from 1 to 3 substituents independently selected from the        group consisting of halogen, amino, oxo, C₁₋₈ alkyl, C₁₋₈        haloalkyl, hydroxy, C₁₋₈ alkoxy, heterocycloalkyl, heteroaryl,        and heteroaryl-C₁₋₄ alkyl;    -   each R^(4a) or R^(4b) is independently hydrogen or C₁₋₄ alkyl,        optionally substituted with from 1 to 2 substituents        independently selected from the group consisting of halogen,        hydroxyl, alkoxy, heterocyclyl, oxo, amino and carboxyl;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        and C₁₋₄ alkyl;    -   the subscript n is an integer from 0 to 2;    -   the wavy line indicates the point of attachment to the rest of        the molecule;    -   and pharmaceutically acceptable salts, esters and prodrugs        thereof.

In another group of embodiments, the R¹ is C₂₋₈ alkynyl.

In another embodiment, the compound has the formula:

and the invention contemplates pharmaceutically acceptable salts, estersand prodrugs thereof.

In another group of embodiments, R¹ is halogen.

In another embodiment, the compound is selected from the groupconsisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, R⁴ is hydrogen.

In another embodiment, the compound has the formula:

and pharmaceutically acceptable salts, esters and prodrugs thereof.

In another group of embodiments, the compound of the invention is in anisolated and purified form.

Within the present invention, the compounds provided in the examplesbelow are each preferred embodiments, along with their pharmaceuticallyacceptable salts, esters and prodrugs thereof. Preferred examples ofcompounds of formula (I) include:

5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-oxomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(6-oxopyridazin-1(6H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxo-6-methylpyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(1,1-dioxo-3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(1,3-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2,5-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(methylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-chloro-N-((1-(2-(methylsulfinyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1-dioxo-thiomorpholin-4-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(2-hydroxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-hydroxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-methoxycarbonyl-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-thioxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide;

5-Ethynyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-(cyanoimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-(methylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-(4-methoxyphenylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(4-(2-(acetylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

4-Chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-pyrrole-2-carboxamide;

5-Chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-pyrrole-2-carboxamide;

5-Chloro-N-((1-(4-(1,1-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(5-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(4-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide

N-((1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(4-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

N-((1-(4-(4-acetamido-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxopiperidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-5-carboxamide;

5-Chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((2-(methylsulfonyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((2-(methylsulfinyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(4-ethyl-2,3-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(4-(2-(Carbamoylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

5-Chloro-N-((2-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfinyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfonyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfinyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfonyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(2-methoxyethoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

(R)-5-Chloro-N-((1-(2-(2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

(S)-5-Chloro-N-((1-(2-(2,3-dihydroxypropoxy)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(2-hydroxypyridin-4-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(2-(6-hydroxypyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

N-((1-(2-(6-Aminopyridin-3-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide;

5-Chloro-N-((1-(4-(4-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(6-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;

5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide;and

5-Chloro-N-((1-(4-(6-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide.

All of the preferred, more preferred, and most preferred compoundslisted above are selective inhibitors of Factor Xa.

b. Compositions

The present invention further provides compositions comprising one ormore compounds of formula (I) or a pharmaceutically acceptable salt,ester or prodrug thereof, and a pharmaceutically acceptable carrier. Itwill be appreciated that the compounds of formula (I) in this inventionmay be derivatized at functional groups to provide prodrug derivativeswhich are capable of conversion back to the parent compounds in vivo.Examples of such prodrugs include the physiologically acceptable andmetabolically labile ester derivatives, such as methoxymethyl esters,methylthiomethyl esters, or pivaloyloxymethyl esters derived from ahydroxyl group of the compound or a carbamoyl moiety derived from anamino group of the compound. Additionally, any physiologicallyacceptable equivalents of the compounds of formula (I), similar tometabolically labile esters or carbamates, which are capable ofproducing the parent compounds of formula (I) in vivo, are within thescope of this invention.

If pharmaceutically acceptable salts of the compounds of this inventionare utilized in these compositions, those salts are preferably derivedfrom inorganic or organic acids and bases. Included among such acidsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

Furthermore, the basic nitrogen-containing groups may be quaternizedwith agents like lower alkyl halides, such as methyl, ethyl, propyl andbutyl chlorides, bromides and iodides; dialkyl sulfates, such asdimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;aralkyl halides, such as benzyl and phenethyl bromides and others. Wateror oil-soluble or dispersible products are thereby obtained.

The compounds utilized in the compositions and methods of this inventionmay also be modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem, etc.), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a sterile liquid, such as oil, water, alcohol, andcombinations thereof. Pharmaceutically suitable surfactants, suspendingagents or emulsifying agents, may be added for oral or parenteraladministration. Suspensions may include oils, such as peanut oil, sesameoil, cottonseed oil, corn oil and olive oil. Suspension preparation mayalso contain esters of fatty acids, such as ethyl oleate, isopropylmyristate, fatty acid glycerides and acetylated fatty acid glycerides.Suspension formulations may include alcohols, such as ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil andpetrolatum, and water may also be used in suspension formulations.

Pharmaceutically acceptable carriers that may be used in thesecompositions include ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffersubstances, such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally or intravenously. The formulations of the invention may bedesigned as short-acting, fast-releasing, or long-acting. Still further,compounds can be administered in a local rather than systemic means,such as administration (e.g., injection) as a sustained releaseformulation.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmultidose containers.

The pharmaceutical compositions of this invention may be in any orallyacceptable dosage form, including capsules, tablets, aqueous suspensionsor solutions. In the case of tablets for oral use, carriers that arecommonly used include lactose and corn starch. Lubricating agents, suchas magnesium stearate, are also typically added. For a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may bein the form of suppositories for rectal administration. These may beprepared by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also be in atopical form, especially when the target of treatment includes areas ororgans readily accessible by topical application, including diseases ofthe eye, the skin, or the lower intestinal tract. Suitable topicalformulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters, wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative, such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment, such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons and/or other conventional solubilizing ordispersing agents.

Any of the above dosage forms containing effective amounts are withinthe bounds of routine experimentation and within the scope of theinvention. A therapeutically effective dose may vary depending upon theroute of administration and dosage form. The preferred compound orcompounds of the invention is a formulation that exhibits a hightherapeutic index. The therapeutic index is the dose ratio between toxicand therapeutic effects which can be expressed as the ratio between LD₅₀and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and theED₅₀ is the dose therapeutically effective in 50% of the population. TheLD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures inanimal cell cultures or experimental animals.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers and dosage forms aregenerally known to those skilled in the art and are included in theinvention. It should be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex and diet of the patient, and thetime of administration, rate of excretion, drug combination, judgment ofthe treating physician and severity of the particular disease beingtreated. The amount of active ingredient(s) will also depend upon theparticular compound and other therapeutic agent, if present, in thecomposition.

c. Methods of Use

The invention provides methods of inhibiting or decreasing Factor Xaactivity as well as treating or ameliorating a Factor Xa associatedstate, symptom, disorder or disease in a patient in need thereof (e.g.,human or non-human). In one embodiment, the invention provides methodsfor preventing or treating a condition in a mammal characterized byundesired thrombosis comprising the step of administering to the mammala therapeutically effective amount of a compound of the presentinvention. Such conditions include, but are not limited, to acutecoronary syndrome, myocardial infarction, unstable angina, refractoryangina, occlusive coronary thrombus occurring post-thrombolytic therapyor post-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, conditions requiring the fitting of prostheticdevices, and the like.

“Treating” within the context of the invention means an alleviation ofsymptoms associated with a disorder or disease, or halt of furtherprogression or worsening of those symptoms, or prevention or prophylaxisof the disease or disorder.

The term “mammal” includes organisms which express Factor Xa. Examplesof mammals include mice, rats, cows, sheep, pigs, goats, horses, bears,monkeys, dogs, cats and, preferably, humans. Transgenic organisms whichexpress Factor Xa are also included in this definition.

The inventive methods comprise administering an effective amount of acompound or composition described herein to a mammal or non-humananimal. As used herein, “effective amount” of a compound or compositionof the invention includes those amounts that antagonize or inhibitFactor Xa. An amount which antagonizes or inhibits Factor Xa isdetectable, for example, by any assay capable of determining Factor Xaactivity, including the one-described below as an illustrative testingmethod. Effective amounts may also include those amounts which alleviatesymptoms of a Factor Xa associated disorder treatable by inhibitingFactor Xa. Accordingly, “antagonists of Factor Xa” include compoundswhich interact with the Factor Xa and modulate, e.g., inhibit ordecrease, the ability of a second compound, e.g., another Factor Xaligand, to interact with the Factor Xa. The Factor Xa binding compoundsare preferably antagonists of Factor Xa. The language “Factor Xa bindingcompound” (e.g., exhibits binding affinity to the receptor) includesthose compounds which interact with Factor Xa resulting in modulation ofthe activity of Factor Xa. Factor Xa binding compounds may be identifiedusing an in vitro (e.g., cell and non-cell based) or in vivo method. Adescription of an in vitro method is provided below.

The amount of compound present in the methods and compositions describedherein should be sufficient to cause a detectable decrease in theseverity of the disorder, as measured by any of the assays described inthe examples. The amount of Factor Xa modulator needed will depend onthe effectiveness of the modulator for the given cell type and thelength of time required to treat the disorder. In certain embodiments,the compositions of this invention may further comprise anothertherapeutic agent. When a second agent is used, the second agent may beadministered either as a separate dosage form or as part of a singledosage form with the compounds or compositions of this invention. Whileone or more of the inventive compounds can be used in an application ofmonotherapy to treat a disorder, disease or symptom, they also may beused in combination therapy, in which the use of an inventive compoundor composition (therapeutic agent) is combined with the use of one ormore other therapeutic agents for treating the same and/or other typesof disorders, symptoms and diseases. Combination therapy includesadministration of the two or more therapeutic agents concurrently orsequentially. The agents may be administered in any order.Alternatively, the multiple therapeutic agents can be combined into asingle composition that can be administered to the patient. Forinstance, a single pharmaceutical composition could comprise thecompound or pharmaceutically acceptable salt, ester or prodrug thereofaccording to the formula (I), another therapeutic agent (e.g.,methotrexate) or a pharmaceutically acceptable salt, ester or prodrugthereof, and a pharmaceutically acceptable excipient or carrier.

The invention comprises a compound having the formula (I), a method formaking an inventive compound, a method for making a pharmaceuticalcomposition from at least one inventive compound and at least onepharmaceutically acceptable carrier or excipient, and a method of usingone or more inventive compounds to treat a variety of disorders,symptoms and diseases (e.g., inflammatory, autoimmune, neurological,neurodegenerative, oncology and cardiovascular), such as RA,osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructivepulmonary disease COPD and MS. The inventive compounds and theirpharmaceutically acceptable salts and/or neutral compositions may beformulated together with a pharmaceutically acceptable excipient orcarrier and the resulting composition may be administered in vivo tomammals, such as men, women and animals, to treat a variety ofdisorders, symptoms and diseases. Furthermore, the inventive compoundscan be used to prepare a medicament that is useful for treating avariety of disorders, symptoms and diseases.

d. Kits

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treat states,disorders, symptoms and diseases where Factor Xa plays a role.

EXAMPLES

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2005, Volumes 1-65.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C. to about 75° C.

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Alliancechromatography system with a 2695 Separation Module (Milford, Mass.).The analytical columns were C-18 SpeedROD RP-18E Columns from Merck KGaA(Darmstadt, Germany). Alternately, characterization was performed usinga Waters Unity (UPLC) system with Waters Acquity UPLC BEH C-18 2.1 mm×15mm columns. A gradient elution was used, typically starting with 5%acetonitrile/95% water and progressing to 95% acetonitrile over a periodof 5 minutes for the Alliance system and 1 minute for the Acquitysystem. All solvents contained 0.1% trifluoroacetic acid (TFA).Compounds were detected by ultraviolet light (UV) absorption at either220 or 254 nm. HPLC solvents were from EMD Chemicals, Inc. (Gibbstown,N.J.). In some instances, purity was assessed by thin layerchromatography (TLC) using glass backed silica gel plates, such as, forexample, EMD Silica Gel 60 2.5 cm×7.5 cm plates. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two Agilent 1100series LCMS instruments with acetonitrile/water as the mobile phase. Onesystem using TFA as the modifier and measures in positive ion mode andthe other uses either formic acid or ammonium acetate and measures inboth positive and negative ion modes.

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 400 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.

The purity of some of the invention compounds may be assessed byelemental analysis (Robertson Microlit, Madison N.J.).

Melting points may be determined on a Laboratory Devices Mel-Tempapparatus (Holliston, Mass.).

Preparative separations were carried out using either an Sq16x or anSg100c chromatography system and prepackaged silica gel columns allpurchased from Teledyne Isco, (Lincoln, Nebr.). Alternately, compoundsand intermediates were purified by flash column chromatography usingsilica gel (230-400 mesh) packing material, or by HPLC using a C-18reversed phase column. Typical solvents employed for the Isco systemsand flash column chromatography were dichloromethane, methanol, ethylacetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.Typical solvents employed for the reverse phase HPLC were varyingconcentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

The following abbreviations are used throughout the Examples:

μL=microliter

μM=micromolar

aq.=aqueous

BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate

CaCl₂=calcium chloride

CH₂Cl₂=dichloromethane

CH₃CN=acetonitrile

CuI=copper iodide

DIEA=diisopropyl ethyl amine

DMF=dimethyl formamide

DMSO=dimethyl sulfoxide

EtOAc=ethyl acetate

g=gram

h=hour

HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate

HPLC=high pressure liquid chromatography

IC₅₀=The concentration of an inhibitor that is required for 50%inhibition of an enzyme in vitro

IV=intravenous

K₂CO₃=potassium carbonate

K₃PO₄=Potassium phosphate

kg=kilogram

M=molar

m/z=mass to charge ratio

mCPBA=m-chloroperoxybenzoic acid

MeOH=methanol

mg=milligram

MHz=Mega Hertz

min=minute

mL=milliliter

mm=millimeter

mM=millimolar

mmol=millimole

mOD/min=millioptical density units per minute

MP-carbonate=Macroporour triethylammonium methylpolystyrene carbonate(0.5% inorganic antistatic agent)

MS=Mass Spec

N=Normal

NaCl=sodium chloride

NaH=sodium hydride

NaHCO₃=sodium bicarbonate

NaN₃=sodium azide

NaSMe=sodium methylthiolate

NaSO₄=sodium sulfate

nBuOH=n-butanol

ng=nanogram

nm=nanometer

nM=nanomolar

Pd(PPh₃)₄=tetrakis-(triphenylphosphan)-palladium

PEG=polyethylene glycol

pM=picomolar

PO=oral

PPh₃ or Ph₃P=triphenyl phosphine

Ra—Ni=Rainey Nickel

SOCl2=thionyl chloride

TEA=triethylamine

TSC=trisodium citrate

General Methods

The following synthetic reaction schemes are merely illustrative of somemethods by which the compounds of the present invention can besynthesized, and various modifications to these synthetic reactionschemes can be made and will be suggested to one skilled in the arthaving referred to the disclosure contained in this application.

Scheme I represents the general synthetic method for preparing compoundshaving formula I-4. According to Scheme I, the alcohol I-1 istransformed to the amine I-2 via a three-step procedure: (1)halogenation such as with thionyl chloride, (2) displacement of thehalide with an azide such as sodium azide, and (3) reduction of theazide to form the amine I-2 by catalytic hydrogenation. The amine I-2 isthen coupled with the acid Z-COOH via conventional amide formationmethods, such as using coupling reagents like BOP, to form compound I-3,wherein Z is as defined herein. Displacement of the iodo group ofcompound I-3 with the corresponding R⁵ moiety, such as under basicconditions, such as with K₂CO₃, and in the presence of8-hydroxyquinoline and CuI provides the desired compound I-4, wherein Ris as defined herein. Certain R⁵ moieties of compound I-4 may undergofurther modifications. For example, the thio group of Example 6 may beoxidized to form the corresponding sulfoxide and sulfone analogues.Compound I-1 may be obtained using either Scheme 1 or Scheme 2 below.

Compounds having formula II-7 may be prepared according to Scheme II.(1H-imidazol-4-yl)methanol II-1 is converted to(1H-imidazol-4-yl)methanamine II-2 via a three-step procedure andcoupled with Z-COOH to form compound II-3 using conditions similar tothat described above. Meanwhile, selective displacement of the 4-iodogroup of 2-fluoro-1,4-diiodobenzene by R⁵—H such as under basicconditions, such as with K₂CO₃, and in the presence of8-hydroxyquinoline and CuI provides compound II-5. Subsequentdisplacement of the second iodo group with compound II-3 under similarconditions gives compound II-6. Compound II-6 may also be preparedthrough a linear route as exemplified by Scheme 4 below. Displacement ofthe fluoro group with R⁴—H gives the desired product II-7, wherein R⁴ isas defined herein.

Example 15-Cloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(10)

Scheme 1 represents a synthetic method for the synthesis of compound 10.Scheme 2 represents an alternative method for the synthesis of compoundI-1.

Step 1:

A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol),4-(hydroxymethyl)imidazole II-1 (1.20 g, 12.2 mmol), 8-hydroxyquinoline(0.176 g, 1.21 mmol) and K₂CO₃ (1.69 g, 12.2 mmol) in DMSO (12 mL) wasdegassed before being charged with CuI (0.230 g, 1.21 mmol). The mixturein a sealed tube was heated at 130° C. overnight. Water and EtOAc wereadded. The mixture was filtered. The organic layer was separated, thenapplied to a silica gel column, which was eluted with 0-5% MeOH inCH₂Cl₂ to give 4-hydroxymethyl 1-(4-iodophenyl)imidazole I-1 (0.810 g).MS 301.2 (M+H).

Step 2:

The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole I-1 (0.810 g,2.70 mmol) was dissolved in SOCl₂ (6 mL). The solution was stirred atroom temperature for 15 min. It was then concentrated in vacuo. Theresidue was partitioned between EtOAc and 5% aq. NaHCO₃. The organiclayer was separated, dried over Na₂SO₄, concentrated in vacuo to give4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 as a solid (0.780 g). MS318.9 and 320.9 (M+H, Cl pattern).

Step 3:

The compound 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 (0.780 g, 2.45mmol) was dissolved in DMF (10 mL). To the solution, NaN₃ (0.520 g, 8.00mmol) was added. After being stirred at room temperature overnight,water and EtOAc were added. The organic layer was separated, dried overNa₂SO₄, concentrated in vacuo to give 4-azidomethyl1-(4-iodophenyl)imidazole 1-4 as a solid (0.725 g). MS 326.0 (M+H)

Step 4:

A solution of 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 (0.725 g, 2.23mmol) over Ra—Ni (50% aq. slurry, 300 mg) in MeOH (12 mL) washydrogenated under balloon H₂ for 3 h. The mixture was filtrated throughCELITE. The filtrate was concentrated in vacuo to give 4-aminomethyl1-(4-iodophenyl)imidazole I-2 as a solid (0.603 g). MS 300.0 (M+H)

Step 5:

To a mixture of 5-chlorothiophene-2-carboxylic acid 1-5 (0.346 g, 2.13mmol), 4-aminomethyl 1-(4-iodophenyl)imidazole I-2 prepared above (0.578g, 1.93 mmol) and TEA (0.670 mL, 4.82 mmol) in DMF (10 mL), BOP (1.03 g,2.33 mmol) was added. The mixture was then stirred at room temperatureovernight. Water and EtOAc were added. The organic layer was separated,washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated in vacuo to give5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 as a solid (0.832 g), which was found to be pure enough for nextreaction. MS 443.9 and 445.9 (M+H, Cl pattern).

Step 6:

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared above (0.270 g, 0.609 mmol), 2-hydroxypyridine 1-7 (0.115g, 1.21 mmol), 8-hydroxyquinoline (0.041 g, 0.283 mmol) and K₂CO₃ (0.333g, 2.41 mmol) in DMSO (2 mL) was degassed before being charged with CuI(0.058 g, 0.305 mmol). The mixture in a sealed tube was heated at 130°C. overnight. The mixture was then purified by HPLC to give the titlecompound 10 (0.080 g). MS 411.0 and 413.0 (M+H, Cl pattern); ¹H NMR(DMSO-d₆, 400 MHz) δ 9.27 (m, 2H), 8.08 (s, 1H), 7.87 (d, 2H), 7.69 (d,1H), 7.65 (m, 3H), 7.51 (m, 1H), 7.19 (d, 1H), 6.49 (d, 1H), 6.34 (dd,1H), 4.52 (d, 2H).

Example 25-Chloro-N-((1-(4-(3-oxomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(11)

NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To theflask, cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for10 min until no H₂ gas evolved. The thick slurry was then cooled in anice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) indioxane (15 mL) was added. The reaction mixture was heated at reflux for1 h. It was then filtered. The filtrate was concentrated in vacuo togive an oil, which was purified by a short silica gel column, elutedwith EtOAc/MeOH (95/5) to give 3-morpholinone as a white solid (1.9 g).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (33 mg, 0.074 mmol), 3-morpholinone preparedabove (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048 mmol) andK₂CO₃ (30 mg, 0.217 mmol) in DMSO (0.5 mL) was degassed before beingcharged with CuI (14 mg, 0.073 mmol). The mixture in a sealed tube washeated at 130° C. overnight. The mixture was then purified by HPLC togive the title compound (3 mg). MS 417.0 and 419.0 (M+H, Cl pattern).

Example 35-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(12)

To a solution of glycinamide hydrochloride (1.10 g, 10.0 mmol) in 5 NNaOH (6 mL) at room temperature, glyoxal (40% in H₂O, 1.5 mL, 13.1 mmol)was added. The solution was stirred at room temperature overnight. Theproduct was extracted from the aqueous solution with nBuOH, and thenBuOH extract was concentrated in vacuo to give 2-hydroxypyrazine as awhite solid (0.20 g).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (100 mg, 0.23 mmol), 2-hydroxypyrazineprepared above (43 mg, 0.45 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol)and K₂CO₃ (123 mg, 0.89 mmol) in DMSO (1 mL) was degassed before beingcharged with CuI (21 mg, 0.11 mmol). The mixture in a sealed tube washeated at 130° C. overnight. The mixture was then purified by HPLC togive the title compound (15 mg). MS 412.0 and 414.0 (M+H, Cl pattern).

Example 45-Chloro-N-((1-(4-(6-oxopyridazin-1(6H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(13)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (100 mg, 0.23 mmol), 3-hydroxypyridazine (43mg, 0.45 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K₂CO₃ (123 mg,0.89 mmol) in DMSO (1 mL) was degassed before being charged with CuI (19mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titlecompound (15 mg). MS 412.0 and 414.0 (M+H, Cl pattern).

Example 55-chloro-N-((1-(4-(6-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(14)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (100 mg, 0.22 mmol), 2-hydroxy-6-methylpyridine (60 mg, 0.55 mmol),8-hydroxyquinoline (20 mg, 0.14 mmol) and K₂CO₃ (140 mg, 1.01 mmol) inDMSO (3 mL) was degassed with Ar before being charged with CuI (28 mg,0.15 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (4 mg). MS 425.1 and 427.1(M+H, Cl pattern).

Example 65-Chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(15)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (230 mg, 0.518 mmol), 3-thiomorpholinone (121mg, 1.03 mmol), 1,2-trans-diaminocyclohexane (26 μL, 0.21 mmol) andK₃PO₄ (220 mg, 1.04 mmol) in dioxane (2 mL) was degassed with Ar beforebeing charged with CuI (40 mg, 0.21 mmol). The mixture in a sealed tubewas heated at 110° C. overnight. It was then purified by HPLC to givethe title compound (58 mg). MS 433.1 and 435.0 (M+H, Cl pattern).

Example 75-Chloro-N-((1-(4-(1,1-dioxo-3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(16) and5-Chloro-N-((1-(4-(1,3-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(17)

To a solution of5-chloro-N-((1-(4-(3-oxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 6 (56 mg, 0.13 mmol) in acetone (3 mL) at roomtemperature, mCPBA (38 mg, 70-77%, 0.15 mmol) was added. It was stirredat room temperature for 1 h. HPLC showed formation of the sulfone andsulfoxide in a ratio of 2 to 1. The solution was concentrated in vacuo,and the residue was purified by HPLC to give the sulfone (6 mg) and thesulfoxide (3 mg). MS 465.0 and 467.0 (M+H, Cl pattern) for the sulfoneand 449.1 and 451.0 (M+H, Cl pattern) for the sulfoxide.

Example 85-Chloro-N-((1-(4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(18)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (80 mg, 0.18 mmol), tetrahydro-2-pyrimidinone(54 mg, 0.54 mmol), 1,2-trans-diaminocyclohexane (13 μL, 0.11 mmol) andK₃PO₄ (100 mg, 0.47 mmol) in dioxane (1 mL) was degassed with Ar beforebeing charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tubewas heated at 110° C. overnight. It was then purified by HPLC to givethe title compound (4 mg). MS 416.1 and 418.1 (M+H, Cl pattern).

Example 95-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(19)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (80 mg, 0.18 mmol), ethyleneurea (40 mg, 0.47mmol), 1,2-trans-diaminocyclohexane (15 μL, 0.12 mmol) and K₂CO₃ (100mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before being chargedwith CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at110° C. overnight. It was then purified by HPLC to give the titlecompound (5 mg). MS 402.1 and 404.1 (M+H, Cl pattern).

Example 105-Chloro-N-((1-(4-(2,5-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(20)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 prepared in Example 1 (80 mg, 0.18 mmol), glycine anhydride (40 mg,0.35 mmol), 1,2-trans-diaminocyclohexane (30 μL, 0.24 mmol) and K₂CO₃(100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before beingcharged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube washeated at 110° C. overnight. It was then purified by HPLC to give thetitle compound (10 mg). MS 430.1 and 432.1 (M+H, Cl pattern).

Example 115-Chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(21)

A mixture of 2,5-diiodofluorobenzene II-4 (2.00 g, 5.75 mmol),2-hydroxypyridine 1-7 (0.546 g, 5.75 mmol), 8-hydroxyquinoline (0.083 g,0.57 mmol) and K₂CO₃ (1.00 g, 7.25 mmol) in DMSO (10 mL) was degassedbefore being charged with CuI (0.109 g, 0.57 mmol). The mixture in asealed tube was heated at 130° C. overnight. Water and EtOAc were added.The mixture was filtered. The organic layer was separated, then appliedto a silica gel column, which was eluted with 0-70% EtOAc in hexane togive 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 (0.820 g). MS315.8 (M+H).

To a suspension of 4-hydroxymethylimidazole II-1 (1.09 g, 11.1 mmol) inCH₃CN (12 mL), SOCl₂ (5 mL) was added. After being stirred at roomtemperature for 30 min, the suspension became clear. After stirring foradditional 2 h, the solution was concentrated in vacuo to give a solid,which was then dissolved in DMF (15 mL). To the solution, NaN₃ (2.16 g,33.2 mmol) was added. After the mixture was stirred at room temperatureovernight, water and EtOAc were added, then 5% aq. NaHCO₃ was alsoadded. The organic layer was separated, dried over Na₂SO₄, concentratedin vacuo to give 4-azidomethylimidazole as a solid (0.759 g). MS 124.1(M+H).

A mixture of 4-azidomethylimidazole prepared above (0.759 g, 6.17 mmol)and Ra—Ni (50% slurry in H₂O, 900 mg) in MeOH (15 mL) was hydrogenatedunder H₂ balloon overnight. The mixture was then filtered throughCELITE. The filtrate was concentrated in vacuo to give4-aminomethylimidazole II-2 (0.604 g).

To a solution of 5-chlorothiophene-2-carboxylic acid 1-5 (1.10 g, 6.76mmol) and TEA (2.0 mL, 14.4 mmol) in DMF (12 mL), BOP (3.30 g, 7.45mmol) was added. After being mixed for 5 min, the solution was added tothe compound 4-aminomethylimidazole II-2 prepared above (0.604 g, 6.22mmol) in a round bottom flask. The mixture was then stirred at roomtemperature overnight. It was purified by HPLC to give5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (1.52g). MS 242.0 and 244.0 (M+H, Cl pattern).

A mixture of5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1prepared above (0.940 g, 2.64 mmol),1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared above(0.820 g, 2.60 mmol), 8-hydroxyquinoline (0.066 g, 0.45 mmol) and K₂CO₃(0.630 g, 4.56 mmol) in DMSO (8 mL) was degassed with Ar before beingcharged with CuI (0.090 g, 0.47 mmol). The mixture in a sealed tube washeated at 130° C. overnight. It was then purified by HPLC to give thetitle compound (0.480 g). MS 429.0 and 431.0 (M+H, Cl pattern).

Alternatively as shown in Scheme 4,1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared as above,is treated with 4-hydroxymethylimidazole II-1 in the presence of8-hydroxyquinoline, and K₂CO₃ in DMSO. The resulting mixture is degassedbefore being charged with CuI to give4-hydroxymethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-1.The compound 4-1 is treated with thionyl chloride to give4-chloromethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole whichis then treated with NaN₃ to result in4-azidomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-2.The azide 4-2 is reduced with Ph₃P to give4-aminomethyl-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)imidazole 4-3.The compound 4-3 is then treated with 5-chlorothiophene-2-carboxylicacid 1-5 to give the title compound 21.

Example 125-Chloro-N-((1-(2-(methylsulfonyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(22) and5-chloro-N-((1-(2-(methylsulfinyl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(23)

A solution of5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide21 prepared in Example 11 (96 mg, 0.22 mmol) and NaSMe (68 mg, 0.97mmol) in DMSO (2 mL) was heated at 80° C. for 1 h. The mixture waspurified by HPLC to give5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(16 mg). MS 457.0 and 459.0 (M+H, Cl pattern)

To a solution of5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared above (16 mg, 0.035 mmol) in acetone (1 mL), mCPBA (70%, 12 mg,0.049 mmol) was added. After being stirred at room temperature for 30min, the mixture was purified by HPLC to give the sulfoxide (5 mg) andsulfone (3 mg). MS 473.0 and 475.0 (M+H, Cl pattern) for sulfoxide and489.0 and 491.0 (M+H, Cl pattern) for sulfone.

Example 135-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(24)

A solution of5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 11 (70 mg, 0.16 mmol) and thiomorpholine (1 mL) inDMSO (1 mL) was heated at 150° C. for 3 days. The mixture was purifiedby HPLC to give the title compound (25 mg). MS 512.0 and 514.0 (M+H, Clpattern).

Example 145-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(1,1-dioxo-thiomorpholin-4-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(25)

To a solution of5-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-thiomorpholinophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 13 (22 mg, 0.043 mmol) in acetone (2 mL), mCPBA(70%, 32 mg, 0.13 mmol) was added. After being stirred at roomtemperature for 2 h, the mixture was purified by HPLC to give the titlecompound (8 mg). MS 544.1 and 546.1 (M+H, Cl pattern).

Example 155-Chloro-N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(26)

A solution of5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 11 (70 mg, 0.16 mmol) and 2-oxopiperazine (565 mg,5.65 mmol) in DMSO (1 mL) was heated at 150° C. for 2 days. The mixturewas purified by HPLC to give the title compound (14 mg). MS 509.0 and511.0 (M+H, Cl pattern).

Example 165-Chloro-N-((1-(2-(2-hydroxyethylamino)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(27)

A solution of5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 11 (75 mg, 0.17 mmol) and ethanolamine (1.5 mL) inDMSO (1 mL) in a sealed tube was heated at 150° C. overnight. Themixture was purified by HPLC to give the title compound (13 mg). MS470.0 and 472.0 (M+H, Cl pattern).

Example 175-Chloro-N-((1-(2-hydroxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(28)

A solution of5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared in Example 11 (80 mg, 0.19 mmol) and 5 N aq. NaOH (0.5 mL, 2.5mmol) in DMSO (2 mL) in a sealed tube was heated at 130° C. overnight.The mixture was purified by HPLC to give the title compound (5 mg). MS427.0 and 429.0 (M+H, Cl pattern).

Example 185-Chloro-N-((1-(2-methoxycarbonyl-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(29)

To a solution of 2,5-diiodobenzoic acid (1.00 g, 2.67 mmol) in anhydrousMeOH (15 mL) cooled in an ice-bath, SOCl₂ (0.50 mL, 6.85 mmol) wascautiously added (exothermal reaction). After the addition, the solutionwas heated at reflux overnight. It was then concentrated in vacuo togive methyl 2,5-diiodobenzoate (1.04 g).

A mixture of methyl 2,5-diiodobenzoate prepared above (1.04 g, 2.67mmol), 2-hydroxypyridine 1-7 (0.254 g, 2.67 mmol), 8-hydroxyquinoline(0.077 g, 0.53 mmol) and K₃PO₄ (1.13 g, 5.33 mmol) in dioxane (8 mL) wasdegassed with Ar before being charged with CuI (0.101 g, 0.53 mmol). Themixture in a sealed tube was heated at 130° C. overnight. It was thenpurified by HPLC to give 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid(0.220 g). MS 342.0 (M+H).

A mixture of 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid prepared above(220 mg, 0.65 mmol), 4-hydroxymethylimidazole II-1 (126 mg, 1.29 mmol),8-hydroxyquinoline (19 mg, 0.13 mmol) and K₂CO₃ (290 mg, 2.10 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (25 mg,0.13 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoicacid (92 mg). MS 312.1 (M+H).

To a solution of2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoicacid prepared above (92 mg, 0.30 mmol) in MeOH (4 mL) and dioxane (2 mL)at room temperature, (trimethylsilyl)diazomethane (2 M in ether, 0.30mL, 0.60 mmol) was added. After the mixture was stirred at roomtemperature overnight, more (trimethylsilyl)diazomethane (2 M in ether,0.40 mL, 0.80 mmol) was added. After stirring for another day, thesolution was concentrated in vacuo to give a residue. The residue wasdissolved in SOCl₂ (4 mL). The solution was stirred at room temperaturefor 20 min before it was concentrated in vacuo to give a residue, whichwas then dissolved in DMF (3 mL). To the solution, NaN₃ (65 mg, 1.0mmol) was added. After the mixture was stirred at room temperature for 2h, water and EtOAc were added, then 5% aq. NaHCO₃ was added. The organiclayer was separated, dried over Na₂SO₄, concentrated in vacuo to givemethyl2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate(25 mg). MS 351.1 (M+H).

To a solution of methyl2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoateprepared above (25 mg, 0.071 mmol) in THF (1 mL) and H₂O (0.025 mL, 1.4mmol), Ph₃P (64 mg, 0.24 mmol) was added. After being stirred at roomtemperature overnight, the mixture was concentrated in vacuo to givemethyl2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoateas a crude mixture, which was then used in the next transformation. MS325.1 (M+H).

To a solution of 5-chlorothiophene-2-carboxylic acid 1-5 (40 mg, 0.25mmol) and TEA (0.068 mL, 0.49 mmol) in DMF (2 mL), BOP (142 mg, 0.32mmol) was added. After 5 min of mixing, the solution was added to thesample methyl2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoateprepared above. The mixture was then stirred at room temperature for 1 hbefore it was purified by HPLC to give the title compound (4 mg). MS469.0 and 471.0 (M+H, Cl pattern).

Example 195-Chloro-N-((1-(4-(2-thioxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(30)

A mixture of 1,4-diiodobenzene 1-1 (2.00 g, 6.06 mmol),2-hydroxypyridine 1-7 (0.576 g, 6.06 mmol), 8-hydroxyquinoline (0.088 g,0.61 mmol) and K₂CO₃ (0.870 g, 6.30 mmol) in DMSO (8 mL) was degassedwith Ar before being charged with CuI (0.115 g, 0.61 mmol). The mixturein a sealed tube was heated at 130° C. overnight. Water and EtOAc wereadded. The mixture was filtered through CELITE. The organic layer wasseparated, then applied to a silica gel column, which was eluted with0-70% EtOAc in hexane to give 1-(4-iodophenyl)pyridin-2(1H)-one as asolid (0.760 g). MS 298.0 (M+H).

A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared above (0.760 g,2.56 mmol), NaHCO₃ (2.15 g, 25.6 mmol) and P₂S₅ (2.27 g, 10.2 mmol) indioxane (20 mL) was heated at 80° C. overnight. After being cooled toroom temperature, water and CH₂Cl₂ were added. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, concentrated in vacuoto give 1-(4-iodophenyl)pyridine-2(1H)-thione as a solid (0.752 g). MS313.8 (M+H).

A mixture of 1-(4-iodophenyl)pyridine-2(1H)-thione prepared above (65mg, 0.21 mmol),5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1prepared in Example 11 (65 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg,0.069 mmol) and K₂CO₃ (75 mg, 0.54 mmol) in DMSO (2 mL) was degassedwith Ar before being charged with CuI (27 mg, 0.14 mmol). The mixture ina sealed tube was heated at 130° C. overnight. It was then purified byHPLC to give the title compound (15 mg). MS 427.0 and 429.0 (M+H, Clpattern).

Example 20N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide(31)

To a solution of indole-6-carboxylic acid (85 mg, 0.528 mmol),4-aminomethyl 1-(4-iodophenyl)imidazole 1-2 prepared in Example 1 (136mg, 0.455 mmol) and TEA (0.150 mL, 1.08 mmol) in DMF (4 mL), BOP (280mg, 0.633 mmol) was added. After the mixture was stirred at roomtemperature overnight, water and EtOAc were added. The organic layer wasseparated, washed with 5% aq. NaHCO₃, dried over Na₂SO₄, concentrated invacuo to giveN-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide asa crude sample, which was used in the next reaction without furtherpurification. MS 443.0 (M+H).

A mixture ofN-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamideprepared above, 2-hydroxypyridine 1-7 (130 mg, 1.37 mmol),8-hydroxyquinoline (30 mg, 0.21 mmol) and K₂CO₃ (246 mg, 1.78 mmol) inDMSO (2 mL) was degassed before being charged with CuI (43 mg, 0.23mmol). The mixture in a sealed tube was heated at 130° C. overnight. Itwas then purified by HPLC to give the title compound (50 mg). MS 410.1(M+H).

Example 215-Ethynyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(32)

A mixture of ethyl 5-bromo-thiophene-2-carboxylate (500 mg, 2.13 mmol),trimethylsilylacetylene (0.445 mL, 3.2 mmol), Pd(PPh₃)₄ (15 mg) and CuI(10 mg) in diisopropylamine (10 mL) was heated at 80° C. for 2 h. Afterbeing cooled to room temperature, the mixture was filtered throughCELITE, and the filtrate was poured into water. The product wasextracted with EtOAc. The EtOAc solution was washed with brine, driedover MgSO₄, concentrated in vacuo to give ethyl5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate (529 mg). MS 253(M+H).

To a solution of ethyl5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate prepared above(529 mg, 2.10 mmol) in THF (20 mL), IN aq. LiOH (7.0 mL, 7.0 mmol) wasadded. After the mixture was stirred at 40° C. overnight, it was pouredinto water. The aqueous solution was acidified with 1N HCl to pH 1. Theproduct was extracted with EtOAc. The EtOAc solution was washed withbrine, dried over MgSO₄, concentared in vacuo to give5-ethynyl-thiophene-2-carboxylic acid (316 mg). MS 153 (M+H).

A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared in Example 19(1.00 g, 3.37 mmol), 4-hydroxymethylimidazole II-1 (0.330 g, 3.37 mmol),8-hydroxyquinoline (0.073 g, 0.50 mmol) and K₂CO₃ (1.00 g, 7.25 mmol) inDMSO (7 mL) was degassed with Ar before being charged with CuI (0.100 g,0.52 mmol). The mixture in a sealed tube was heated at 130° C.overnight. Water and EtOAc were added. The mixture was filtered throughCELITE. The organic layer was separated, dried over Na₂SO₄, concentratedin vacuo. The residue was purified by HPLC to give1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (335mg). MS 268 (M+H).

To a suspension of1-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-oneprepared above (335 mg, 1.25 mmol) in CH₃CN (20 mL), SOCl₂ (5.0 mL) wasadded. After the mixture was stirred at room temperature for 2 h, it wasconcentrated in vacuo. The residue was then dissolved in DMF (20 mL). Tothe solution, NaN₃ (244 mg, 3.75 mmol) was added. After the mixture wasstirred at room temperature overnight, water and EtOAc were added. Theorganic layer was separated, washed with 5% aq. NaHCO₃, dried overNa₂SO₄, concentrated in vacuo to give1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (203mg). MS 293 (M+H).

To a solution of1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one preparedabove (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6 mL), SnCl₂ 2H₂O(343 mg, 1.52 mmol) was added. After the mixture was heated to refluxfor 1 h, it was concentrated in vacuo. The residue was purified by HPLCto give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one(145 mg). MS 267 (M+H).

To a solution of 5-ethynyl-thiophene-2-carboxylic acid (83 mg, 0.54mmol) and TEA (0.15. mL, 1.1 mmol) in DMF (4 mL), HATU (228 mg, 0.60mmol) was added. After being stirred at room temperature for 30 min, asolution of1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one preparedabove (145 mg, 0.54 mmol) and TEA (0.15 mL, 1.1 mmol) in DMF (8 mL) wasadded. The mixture was stirred at room temperature overnight. It wasthen purified by HPLC to give the title compound (65 mg). MS 401 (M+H).

Example 22(E)-5-chloro-N-((1-(4-(2-(cyanoimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(33)

To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (180 mg, 0.575mmol) in CH₃CN (15 mL), CH₃I (0.50 mL, 8.0 mmol) was added. After beingstirred at room temperature overnight, the mixture was concentrated invacuo to give a solid. The solid was dissolved in CH₃CN (5 mL). To thesolution, cyanamide (200 mg, 4.76 mmol) and hydrazine monohydrate (0.100mL, 2.06 mmol) were added. After being stirred at room temperature for 2h, the mixture was purified by HPLC to give(E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg).

A mixture of (E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25mg, 0.078 mmol),5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (65 mg,0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (75 mg,0.54 mmol) in DMSO (1 mL) was degassed with Ar before being charged withCuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130°C. overnight. It was then purified by HPLC to give the titled compound(10 mg). MS 435.1 and 437.0 (M+H, Cl pattern).

Example 23(E)-5-chloro-N-((1-(4-(2-(methylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(34)

To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (98 mg, 0.31mmol) in CH₃CN (5 mL), CH₃I (0.25 mL, 4.0 mmol) was added. After beingstirred at room temperature overnight, the mixture was concentrated invacuo to give a solid. The solid was dissolved in MeOH (7 mL). To thesolution, CH₃NH₂ (2M in THF, 0.80 mL, 1.6 mmol) was added. After beingstirred at room temperature overnight, the mixture was purified by HPLCto give (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59mg).

A mixture of (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine(59 mg, 0.14 mmol),5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (63 mg,0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (100 mg,0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged withCuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130°C. overnight. It was then purified by HPLC to give the titled compound(15 mg). MS 424.1 and 426.1 (M+H, Cl pattern).

Example 24(E)-5-chloro-N-((1-(4-(2-(4-methoxyphenylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(35)

To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (192 mg, 0.61mmol) in CH₃CN (5 mL), CH₃I (0.40 mL, 6.4 mmol) was added. After beingstirred at room temperature overnight, the mixture was concentrated invacuo to give a solid. The solid was dissolved in DMF (3 mL). To thesolution, p-anisidine (317 mg, 2.6 mmol) was added. After being stirredat 100° C. overnight, the mixture was purified by HPLC to give(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine (90mg).

A mixture of(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine (90mg, 0.17 mmol),5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (62 mg,0.17 mmol), 8-hydroxyquinoline (14 mg, 0.096 mmol) and K₂CO₃ (100 mg,0.72 mmol) in DMSO (2 mL) was degassed with Ar before being charged withCuI (20 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130°C. overnight. It was then purified by HPLC to give the titled compound(25 mg). MS 516.0 and 518.1 (M+H, Cl pattern).

Example 25(E)-N-((1-(4-(2-(acetylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(36)

To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (384 mg, 1.23mmol) in CH₃CN (10 mL), CH₃I (0.80 mL, 12.8 mmol) was added. After beingstirred at room temperature overnight, the mixture was concentrated invacuo to give a solid. The solid was dissolved in DMF (6 mL). To thesolution, NH₃ in MeOH (7N, 3.0 mL, 21.0 mmol) and triethylamine (1.5 mL,10.8 mmol) were added. After being stirred at room temperatureovernight, the mixture was purified by HPLC to give a solid. The solidwas dissolved in pyridine (3 mL) and CH₂Cl₂ (3 mL). To the solution,acetyl chloride (0.200 mL, 2.8 mmol) was added. After being stirred atroom temperature overnight, the mixture was purified by HPLC to give(E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)acetamide (120 mg).

A mixture of (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)acetamide (120mg, 0.27 mmol),5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (109mg, 0.30 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K₂CO₃ (100 mg,0.72 mmol) in DMSO (2 mL) was degassed with Ar before being charged withCuI (24 mg, 0.12 mmol). The mixture in a sealed tube was heated at 130°C. for 5 h. It was then purified by HPLC to give the titled compound (8mg). MS 452.0 and 454.0 (M+H, Cl pattern).

Example 264-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-pyrrole-2-carboxamide(37)

A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol),2-hydroxypyridine 1-7 (1.15 g, 12.1 mmol), 8-hydroxyquinoline (176 mg,1.21 mmol) and K₂CO₃ (1.74 g, 12.6 mmol) in DMSO (16 mL) was degassedwith Ar before being charged with CuI (230 mg, 1.21 mmol). The mixturein a sealed tube was heated at 130° C. overnight. After being cooled toroom temperature, H₂O and EtOAc were added. It was filtered throughcelite. The organic phase was separated, dried over Na₂SO4, concentratedin vacuo. The residue was purified by a silica gel column, eluted withEtOAc in hexanes (0-70% EtOAc) to give 1-(4-iodophenyl)pyridin-2(1H)-one(1.30 g).

To a solution of 1-methyl-2-pyrrolecarboxylic acid (1.03 g, 8.22 mmol)in MeOH (5 mL) and dioxane (5 mL) at room temperature,trimethylsilyldiazomethane (2M in ether, 5.0 mL, 10.0 mmol) was added.After being stirred at room temperature for 1 h, the mixture wasconcentrated in vacuo to give methyl 1-methyl-2-pyrrolecarboxylate as avolatile oil (1.14 g).

To a solution of methyl 1-methyl-2-pyrrolecarboxylate (1.14 g, 8.22mmol) in ether (10 mL) at 0° C., SO₂Cl₂ (0.800 mL, 9.96 mmol) was added.After being stirred at room temperature for 15 min, the mixture wasconcentrated in vacuo. The residue was purified by a silica gel column,eluted with 5% EtOAc in hexane to give methyl4-chloro-1-methyl-1H-pyrrole-2-carboxylate (0.13 g). The fractionscontaining methyl 5-chloro-1-methyl-1H-pyrrole-2-carboxylate werefurther purified by HPLC to give the 5-chloro-isomer.

To a solution of methyl 4-chloro-1-methyl-1H-pyrrole-2-carboxylate (130mg, 0.75 mmol) in MeOH (4 mL), aq. 1N NaOH (3 mL) was added. After beingstirred at room temperature overnight, the mixture was acidified with 1NHCl to pH 1-2. The product was extracted with EtOAc. The EtOAc phase wasseparated, dried over Na₂SO₄, concentrated in vacuo to give4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid as a solid (111 mg).

To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (55 mg,0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in DMF (2 mL), BOP(217 mg, 0.49 mmol) was added. After 5 min of stirring, a solution of4-aminomethylimidazole II-2 (100 mg, 1.03 mmol) in DMF (2 mL) was added.After being stirred at room temperature overnight, the mixture waspurified by HPLC to giveN-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide(81 mg).

A mixture ofN-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide(81 mg, 0.23 mmol), 1-(4-iodophenyl)pyridin-2(1H)-one (100 mg, 0.33mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and K₂CO₃ (193 mg, 1.40mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI(21 mg, 0.11 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give the titled compound (25mg). MS 408.1 and 410.1 (M+H, Cl pattern).

Example 275-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-pyrrole-2-carboxamide(38)

The titled compound was prepared analogously to preparation of4-chloro-1-methyl-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-pyrrole-2-carboxamideof Example 26. MS 408.1 and 410.1 (M+H, Cl pattern).

Example 285-chloro-N-((1-(4-(1,1-dioxothiomorpholino)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carbxamide(39)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (56 mg, 0.10 mmol), 1,4-butanesultam (52 mg, 0.38 mmol),8-hydroxyquinoline (6 mg, 0.040 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed before being charged with CuI (10 mg, 0.052mmol). The mixture in a sealed tube was heated at 130° C. overnight. Themixture was then purified by HPLC to give the titled compound (10 mg).MS 451.1 and 453.1 (M+H, Cl pattern).

Example 295-chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(40)

A mixture of 2,5-diiodofluorobenzene II-4 (2.50 g, 7.18 mmol),4-hydroxymethylimidazole hydrochloride (0.967 g, 7.18 mmol),8-hydroxyquinoline (0.104 g, 0.717 mmol) and K₂CO₃ (2.00 g, 14.5 mmol)in DMSO (12 mL) was degassed with Ar before being charged with CuI(0.136 g, 0.716 mmol). The mixture in a sealed tube was heated at 130°C. overnight. After being cooled to room temperature, H₂O and EtOAc wereadded. It was filtered through celite. The organic phase was separated,dried over Na₂SO₄, concentrated in vacuo. The residue was purified by asilica gel column, eluted with MeOH in CH₂Cl₂ (0-5% MeOH) to give(1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol (0.39 g).

To a suspension of (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol(0.39 g, 1.23 mmol) in CH₃CN (7 mL), SOCl₂ (2.5 mL) was added. Upon theaddition, the suspension became clear. It was then concentrated invacuo. The residue was dissolved in DMF (7 mL), NaN₃ (0.32 g, 4.92 mmol)was added. The mixture was stirred at room temperature overnight. H₂Oand EtOAc were added. The organic phase was separated, washed with 5%NaHCO₃, dried over Na₂SO₄, concentrated in vacuo. The residue wasdissolved in MeOH (6 mL), Ra—Ni (50% slurry in H2O, ˜200 mg) was added.The mixture was hydrogenated under balloon H₂ for 2 h. It was thenfiltered through celite. The filtrate was concentrated in vacuo to give(1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine as a solid(0.268 g).

To a solution of 5-chloro-2-thiophenecarboxylic acid 1-5 (165 mg, 1.01mmol) and triethylamine (0.300 mL, 2.16 mmol) in DMF (5 mL), BOP (472mg, 1.07 mmol) was added. After 5 min of stirring, a solution of(1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanamine (268 mg, 0.845mmol) in DMF (4 mL) was added. The mixture was stirred at roomtemperature overnight. H₂O and EtOAc were added. The organic phase wasseparated, washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated invacuo. The residue was purified by HPLC to give5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(83 mg).

A mixture of5-chloro-N-((1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(83 mg, 0.14 mmol), 2-hydroxypyridine 1-7 (30 mg, 0.31 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture was heated at 130° C. in a sealed tube for 4 h.It was then purified by HPLC to give the titled compound (8 mg). MS429.0 and 431.0 (M+H, Cl pattern).

Example 305-chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(41)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (150 mg, 0.34 mmol), 3-methoxy-2-hydroxypyridine (85 mg, 0.68 mmol),8-hydroxyquinoline (20 mg, 0.14 mmol) and K₂CO₃ (100 mg, 0.72 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (25 mg,0.13 mmol). The mixture in a sealed tube was heated at 130° C. for 4 h.The mixture was then purified by HPLC to give the titled compound (99mg). MS 441.0 and 443.0 (M+H, Cl pattern)

Example 315-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(42)

To a solution of5-chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(75 mg, 0.14 mmol) in CH₂Cl₂ (4 mL), BBr₃ (0.365 mL, 3.8 mmol) wasadded. The mixture was stirred at room temperature for 1 h. It wasconcentrated in vacuo. The residue was purified by HPLC to give thetitled compound (40 mg). MS 427.0 and 429.0 (M+H, Cl pattern).

Example 325-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(43)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), 3-fluoro-2-hydroxypyridine (46 mg, 0.40 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube, was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (8 mg). MS 429.0 and 431.0 (M+H, Cl pattern).

Example 335-chloro-N-((1-(4-(3-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(44)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), 2-hydroxy-3-methylpyridine (45 mg, 0.41 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (10 mg). MS 425.0 and 427.0 (M+H, Cl pattern).

Example 345-chloro-N-((1-(4-(5-methyl-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(45)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (56 mg, 0.13 mmol), 2-hydroxy-5-methylpyridine (45 mg, 0.41 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (8 mg). MS 425.0 and 427.0 (M+H, Cl pattern).

Example 355-chloro-N-((1-(4-(4-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(46)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), 2,4-dihydroxypyridine (45 mg, 0.41 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (6 mg). MS 427.0 and 429.0 (M+H, Cl pattern).

Example 365-chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(47)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), uracil (46 mg, 0.41 mmol), 8-hydroxyquinoline(10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in DMSO (1 mL) wasdegassed with Ar before being charged with CuI (15 mg, 0.079 mmol). Themixture in a sealed tube was heated at 130° C. overnight. The mixturewas then purified by HPLC to give the titled compound (25 mg). MS 428.0and 430.0 (M+H, Cl pattern).

Example 37N-((1-(4-(4-amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(48)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), cytosine (46 mg, 0.41 mmol), 8-hydroxyquinoline(10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) in DMSO (1 mL) wasdegassed with Ar before being charged with CuI (15 mg, 0.079 mmol). Themixture in a sealed tube was heated at 130° C. overnight. The mixturewas then purified by HPLC to give the titled compound (10 mg). MS 427.1and 429.1 (M+H, Cl pattern).

Example 385-chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(49)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), 3-methyluracil (60 mg, 0.48 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (60 mg, 0.43 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (15 mg). MS 442.2 and 444.2 (M+H, Cl pattern).

Example 39N-((1-(4-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(50)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (80 mg, 0.18 mmol), 5-fluorocytosine (60 mg, 0.46 mmol),8-hydroxyquinoline (12 mg, 0.083 mmol) and K₂CO₃ (60 mg, 0.43 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (15 mg). MS 445.2 and 447.2 (M+H, Cl pattern).

Example 40N-((1-(4-(4-acetamido-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(51)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (80 mg, 0.18 mmol), N4-acetylcytosine (65 mg, 0.42 mmol),8-hydroxyquinoline (12 mg, 0.083 mmol) and K₂CO₃ (60 mg, 0.43 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (3 mg). MS 469.3 and 471.2 (M+H, Cl pattern).

Example 415-chloro-N-((1-(4-(2-oxopiperidin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(52)

A mixture of1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-onehydrochloride (60 mg, 0.20 mmol) and Pd—C (10%, 31 mg) in MeOH (6 mL)was hydrogenated under balloon H₂ overnight. It was then filteredthrough celite. The filtrate was concentrated in vacuo to give1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg).

To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (43 mg, 0.26mmol) and triethylamine (0.200 mL, 1.43 mmol) in DMF (2 mL), BOP (130mg, 0.29 mmol) was added. After 5 min of stirring, the solution wasadded to a solid sample of1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)piperidin-2-one (54 mg,0.18 mmol) in a flask. After being stirred at room temperature for 2 h,the mixture was purified by HPLC to give the titled compound (45 mg). MS415.1 and 417.1 (M+H, Cl pattern).

Example 425-chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(53)

A mixture of 2-fluoro-4-iodoaniline (3.00 g, 12.6 mmol),2-hydroxypyridine 1-7 (1.20 g, 12.6 mmol), 8-hydroxyquinoline (0.184 ,g, 1.26 mmol) and K₂CO₃ (3.49 g, 25.3 mmol) in DMSO (20 mL) was degassedwith Ar before being charged with CuI (0.241 g, 1.27 mmol). The mixturein a sealed tube was heated at 130° C. overnight. After being cooleddown to room temperature, H₂O and nBuOH were added. The organic phasewas separated, concentrated in vacuo to give1-(4-amino-3-fluorophenyl)pyridin-2(1H)-one as a solid (2.31 g).

To a solution of trifluoroacetic anhydride (10 mL, 71 mmol) in CH₂Cl₂(25 mL) cooled at 0° C., H₂O₂ (50% aq., 4.4 mL, 72 mmol) was addeddropwise. After stirring at 0° C. for 1 h, the sample of1-(4-amino-3-fluorophenyl)pyridin-2(1H)-one (2.31 g, 11.3 mmol) wasadded in solid form portion by portion. After addition, the mixture wasgradually removed from 0° C. to room temperature, and it was stirred atroom temperature overnight. The solvent was removed in vacuo. To theresidue, H₂O was added to induce precipitation, which was collected anddried on vacuum to give 1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one(1.37 g).

To a suspension of 1-(3-fluoro-4-nitrophenyl)pyridin-2(1H)-one (0.70 g,2.99 mmol) in anhydrous THF (6 mL) at room temperature, a pre-mixedsolution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH (60%, 157mg, 3.92 mmol) in anhydrous THF (8 mL) was added. After addition, thesuspension became clear. The mixture was stirred at room temperatureovernight. HPLC showed that the reaction was incomplete. Anotherpre-mixed solution of 1-piperidineethanol (0.40 mL, 3.02 mmol) and NaH(60%, 157 mg, 3.92 mmol) in anhydrous THF (5 mL) was added. After 1 h ofstirring, the reaction was completed. H₂O and EtOAc were added. Theorganic phase was separated, washed with 5% NaHCO₃, dried over Na₂SO₄,concentrated in vacuo to give1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.74g).

A mixture of1-(4-nitro-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.37 g,1.08 mmol) and Pd—C (10%, 65 mg) in MeOH (15 mL) containing 6N HCl (0.5mL) was hydrogenated on a Parr shaker under 45 psi of H₂ overnight. Itwas then filtered through celite. The filtrate was concentrated in vacuoto five 1-(4-amino-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one(0.44 g).

To a solution of1-(4-amino-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (0.44 g,1.08 mmol) in conc. HCl (3 mL) at 0° C., a solution of NaNO₂ (75 mg,1.08 mmol) in H₂O (2 mL) was added dropwise. After 30 min of stirring at0° C., NaI (0.76 g, 5.07 mmol) in H₂O (2 mL) was added. After beingstirred at 0° C. for 30 min, the mixture was removed to room temperatureand was stirred at room temperature for 4 h. The solution was basifiedwith 5 N NaOH to pH 10-12. The product was extracted with EtOAc, washedwith 5% NaHCO₃, dried over Na₂SO₄, concentrated in vacuo. The residuewas purified by HPLC to give1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116 mg).

A mixture of1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116 mg,0.22 mmol), N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide3-1 (85 mg, 0.24 mmol), 8-hydroxyquinoline (14 mg, 0.10 mmol) and K₂CO₃(200 mg, 1.45 mmol) in DMSO (3 mL) was degassed with Ar before beingcharged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube washeated at 130° C. overnight. It was then purified by HPLC to give thetitled compound (10 mg). MS 538.2 and 540.2 (M+H, Cl pattern).

Example 43N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-1H-indole-5-carboxamide(54)

To a solution of indole-5-carboxylic acid (40 mg, 0.25 mmol) andtriethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg, 0.30mmol) was added. After 5 min of stirring,1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-onehydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred atroom temperature overnight. It was then purified by HPLC to give thetitled compound (30 mg). MS 410.2 (M+H).

Example 445-chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(55)

To a suspension of ethyl 2-mercapto-1H-imidazole-4-carboxylate (4.00 g,23.3 mmol) in acetone (30 mL) at room temperature, MeI (6 mL, 96.3 mmol)was added. During first 10 min of stirring, the suspension became clear,then it turned cloudy as product began to precipitate out. After beingstirred at room temperature overnight, the precipitate was collected,dried on vacuum to give ethyl 2-(methylthio)-1H-imidazole-4-carboxylate(3.47 g).

A mixture of 1,4-diiodobenzene 1-1 (4.00 g, 12.1 mmol), ethyl2-(methylthio)-1H-imidazole-4-carboxylate (2.26 g, 12.1 mmol),8-hydroxyquinoline (270 mg, 1.86 mmol) and K₂CO₃ (3.40 g, 24.6 mmol) inDMSO (12 mL) was degassed with Ar before being charged with CuI (345 mg,1.82 mmol). The mixture in a sealed tube was heated at 130° C. for 3days. After cooling down, H₂O and EtOAc were added. After being filteredthrough celite, the organic phase was separated, dried over Na₂SO₄,concentrated in vacuo. The residue was purified by a silica gel column,eluted with EtOAc in hexane (10-35% EtOAc) to give ethyl1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g).

To a solution of ethyl1-(4-iodophenyl)-2-(methylthio)-1H-imidazole-4-carboxylate (0.49 g, 1.26mmol) in anhydrous THF (10 mL) at room temperature, LiBH₄ (2M in THF,3.2 mL, 6.4 mmol) was added. The mixture was stirred at room temperatureovernight. H₂O and EtOAc were added. The organic phase was separated,washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated in vacuo to give(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g).

To a solution of(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanol (0.41 g, 1.18mmol) in anhydrous dioxane (10 mL), diphenylphosphoryl azide (0.80 mL,3.71 mmol) and DBU (0.600 mL, 4.02 mmol) were added. The mixture in asealed tube was heated at 110° C. for 3 h. After being cooled down, H₂Oand EtOAc were added. The organic phase was separated, washed with 5%NaHCO₃, dried over Na₂SO₄, concentrated in vacuo. The residue waspurified by a silica gel column, eluted with EtOAc in hexane (0-20%EtOAc) to give4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.39 g).

To a solution of4-(azidomethyl)-1-(4-iodophenyl)-2-(methylthio)-1H-imidazole (0.26 g,0.70 mmol) in EtOAc (10 mL), Tin(II) chloride dihydrate (0.63 g, 2.8mmol) was added. The mixture was heated at reflux for 10 min. Afterbeing cooled down, 1N NaOH (10 mL) was added. The white precipitate wasfiltered off through celite. The EtOAc phase was separated, dried overNa₂SO₄, concentrated in vacuo to give(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine (127 mg).

To a solution of 5-chloro-thiophene-2-carboxylic acid 1-5 (72 mg, 0.44mmol) and triethylamine (0.150 mL, 1.10 mmol) in DMF (5 mL), BOP (235mg, 0.53 mmol) was added. After 5 min of stirring, the solution wasadded to the sample of(1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methanamine (127 mg,0.37 mmol) in a flask. After being stirred at room temperatureovernight, H₂O and EtOAc were added. The organic phase was separated,washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated in vacuo. Theresidue was dissolved in CH₃CN (8 mL), H₂O (10 mL) was added to induceprecipitation, which was collected and dried on vacuum to give5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(56 mg).

A mixture of5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(56 mg, 0.11 mmol), 2-hydroxypyridine (30 mg, 0.32 mmol),8-hydroxyquinoline (8 mg, 0.055 mmol) and K₂CO₃ (100 mg, 0.72 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give the titled compound (22mg). MS 457.0 and 459.0 (M+H, Cl pattern).

Example 455-chloro-N-((2-(methylsulfonyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(56) and5-chloro-N-((2-(methylsulfinyl)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(57)

To a solution of5-chloro-N-((2-(methylthio)-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(42 mg, 0.092 mmol) in DMF (3 mL), a solution of oxone (155 mg, 0.50mmol) in H₂O (2 mL) was added. The mixture was stirred at roomtemperature overnight. It was then purified by HPLC to give both thesulfone (6 mg) and sulfoxide (5 mg) products. MS 489.0 and 491.0 (M+H,Cl pattern, for sulfone); 473.0 and 475.0 (M+H, Cl pattern, forsulfoxide).

Example 465-chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(58)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (80 mg, 0.18 mmol), pyrazine-2,3-diol (50 mg, 0.44 mmol),8-hydroxyquinoline (12 mg, 0.083 mmol) and K₂CO₃ (100 mg, 0.72 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C. for 4 h.The mixture was then purified by HPLC to give the titled compound (5mg). MS 428.0 and 430.0 (M+H, Cl pattern).

Example 475-chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(59)

A mixture of5-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(30 mg, 0.070 mmol), 2-bromoethanol (0.020 mL, 0.28 mmol) and Cs₂CO₃ (90mg, 0.28 mmol) in DMSO (1 mL) was stirred at 60° C. for 1 h. It was thenpurified by HPLC to give the titled compound (5 mg). MS 471.0 and 473.0(M+H, Cl pattern).

Example 485-chloro-N-((1-(4-(4-ethyl-2,3-dioxopiperazin-1-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(60)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (70 mg, 0.16 mmol), N-ethylpiperazine-2,3-dione (45 mg, 0.32 mmol),N,N′-dimethylethylenediamine (0.020 mL, 0.19 mmol) and K₂CO₃ (65 mg,0.47 mmol) in DMSO (1 mL) and dioxane (1 mL) was degassed with Ar beforebeing charged with CuI (20 mg, 0.10 mmol). The mixture in a sealed tubewas heated at 110° C. overnight. The mixture was then purified by HPLCto give the titled compound (10 mg). MS 458.1 and 460.1(M+H, Clpattern).

Example 49N-((1-(4-(2-(carbamoylimino)pyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(61)

A solution of(E)-5-chloro-N-((1-(4-(2-cyanamidopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(5 mg, 0.011 mmol) in TFA (0.30 mL) and H₂O (0.030 mL) was stirred atroom temperature for 4 h. The solvents were removed in vacuo. Theresidue was purified by HPLC to give the titled compound (2 mg). MS453.0 and 455.1 (M+H, Cl pattern).

Example 505-Chloro-N-((2-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(62)

Step 1:

The mixture of 1,4-diiodobenzene 1-1 (600 mg, 1.8 mmol),2-methyl-1H-imidazole-4-carbaldehyde (200 mg, 1.8 mmol), K₂CO₃ (503 mg,3.6 mmol), CuI (105 mg, 0.55 mmol) and 8-hydroxyquinoline (80 mg, 0.55mol) in 5 mL DMSO and 5 mL dioxane in a sealed tube was stirred for 2days at 120° C. It was cooled to rt, and to it was added 60 mL water.The mixture was stirred for 30 min and filtered through a celite layer.The filtrate was concentrated in vacuo and subjected to reverse phasepreparative HPLC to isolate1-(4-iodophenyl)-2-methyl-1H-imidazole-4-carbaldehyde 5-1. MS found forC₁₁H₉IN₂O (M+H)+313.0.

Step 2:

The compound prepared in above step (140 mg, 0.45 mmol) was dissolved in5 mL methanol and stirred at rt. To it was added NaBH₄ (26 mg, 0.67mmol). The mixture was stirred for 30 min and subjected to preparativeHPLC to isolate (1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methanol5-2. MS found for C₁₁H₉IN₂O (M+H)+315.0.

Step 3:

The compound prepared in above step (126 mg, 0.40 mmol) was dissolved in4 mL dry acetonitrile. To it was added 2 mL thionyl chloride. Themixture was stirred for 40 min and concentrated in vacuo. The dryresidue was then dissolved in 4 mL dry DMF. To it was added sodium azide(>5 eq). The mixture was stirred at rt for 1 hr and diluted with EtOAc.It was washed with brine four times, dried and concentrated in vacuo togive crude 4-(azidomethyl)-1-(4-iodophenyl)-2-methyl-1H-imidazole 5-3.MS found for C₁₁H₁₀IN₅ (M+H)+340.0.

Step 4:

The above prepared crude compound was dissolved in 2 mL ethanol and 2 mLacetic acid. Iron powder (10 eq) was added in. The mixture was stirredin 90° C. bath for 30 min. It was diluted with 20 mL water. The mixturewas well stirred and filtered thru a celite layer. The filtrate wasconcentrated in vacuo and subjected to preparative HPLC to isolate(1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methanamine 5-4. MS foundfor C₁₁H₁₂IN₃ (M+H)+314.0.

Step 5:

The above prepared compound was dissolved in 50 mL methanol and treatedwith MP-carbonate (10 eq). The mixture was gently stirred for 1 hr andfiltered. The filtrate was concentrated in vacuo to give thecorresponding free amine (40 mg, 0.13 mmol). It was dissolved in 2 mLDMF. To it was added DIEA (16 μL, 0.15 mmol) and stirred at RT. In themeantime, 5-chlorothiophene-2-carboxylic acid 1-5 (24 mg, 0.15 mmol) wasdissolved in 2 mL dry DMF. To it was added DIEA (16 μL, 0.15 mmol) andHATU (57 mg, 0.15 mmol). The mixture was stirred for 10 min. It wasadded to the stirred solution of the free amine in DMF. The mixture wasstirred for 20 min and subjected to preparative HPLC to isolate5-chloro-N-((1-(4-iodophenyl)-2-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide5-5. MS found for C₁₆H₁₃ClIN₃OS (M+H)+458.0, 460.0.

Step 6:

The above prepared compound (30 mg, 0.07 mmol) was dissolved in 2 mLDMSO in a sealed tube. To it were added 2-hydroxypyridine 1-7 (20 mg,0.21 mmol), potassium carbonate (48 mg, 0.35 mmol), CuI (8 mg, 0.04mmol) and 8-hydroxyquinoline (6 mg, 0.04 mmol). The mixture was stirredin 130° C. bath for overnight. The mixture was filtered and subjected toreverse phase preparative HPLC to isolate the title compound. MS foundfor C₂₁H₁₇ClN₄O₂S (M+H)+425.1, 427.1.

Example 515-Chloro-N-((5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(63)

Step 1:

1-(4-Iodophenyl)pyridin-2(1H)-one 6-1 (200 mg, 0.67 mmol) was dissolvedin 4 mL DMSO in a sealed tube. To it were added5-methyl-1H-imidazole-4-carbaldehyde (300 mg, 2.7 mmol), K₂CO₃ (470 mg,3.4 mmol), CuI (65 mg, 0.34 mmol) and 8-hydroxyquinoline (50 mg, 0.34mol). The mixture was stirred at 130° C. for 16 hrs. The mixture wasdiluted with 100 mL acetonitrile, well stirred, and filtered through acelite layer. The filtrate was concentrated and subjected to prep HPLCto isolate5-methyl-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazole-4-carbaldehyde6-2. MS found for C₁₆H₁₃N₃O₂ (M+H)+280.1.

Step 2:

The above prepared compound (120 mg, 0.43 mmol) was stirred in 10 mLmethanol at RT. NaBH₄ (25 mg, 0.64 mmol) was added. The mixture wasstirred for 1 hr and subjected to prep HPLC to isolate1-(4-(4-(hydroxymethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one6-3. MS found for C₁₆H₁₅N₃O₂ (M+H)+283.1.

Step 3:

The above prepared compound (80 mg, 0.28 mmol) was stirred in 4 mLacetonitrile and 4 mL thionyl chloride. The mixture was stirred for 1 hrand concentrated in vacuo. The dry residue was then dissolved in 3 mLDMSO. To it was added sodium azide (10 eq). The mixture was stirred for10 min and subjected to prep HPLC to isolate1-(4-(4-(azidomethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one6-4. MS found for C₁₆H₁₄N₆O (M+H)+307.1.

Step 4:

The above prepared compound (48 mg, 0.16 mmol) was dissolved in 1.5 mLethanol and 3 mL acetic acid. To it was added iron powder (45 mg, 0.80mmol). The mixture was stirred at 80° C. for 20 min and diluted withwater. It was filtered and subjected to prep HPLC to isolate1-(4-(4-(aminomethyl)-5-methyl-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one6-5. MS found for C₁₆H₁₆N₄O (M+H)+281.1.

Step 5:

The above prepared compound was dissolved in 30 mL methanol and treatedwith MP-carbonate (10 eq). The mixture was gently stirred for 1 hr andfiltered. The filtrate was concentrated in vacuo to give thecorresponding free amine (45 mg, 0.16 mmol). It was dissolved in 3 mLDMF. To it was added DIEA (36 μL, 0.20 mmol) and stirred at RT. In themeantime, 5-chlorothiophene-2-carboxylic acid 1-5 (32 mg, 0.20 mmol) wasdissolved in 3 mL dry DMF. To it was added DIEA (36 μL, 0.20 mmol) andHATU (76 mg, 0.20 mmol). The mixture was stirred for 10 min. It wasadded to the stirred solution of the free amine in DMF. The mixture wasstirred for 1 hr and subjected to preparative HPLC to isolate the titlecompound. MS found for C₂₁H₁₇ClN₄O₂S (M+H)+425.1, 427.1.

Example 525-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfinyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(64) and5-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfonyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(65)

A mixture of5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(50 mg, 0.10 mmol), 5-fluoro-2-hydroxypyridine (30 mg, 0.26 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (70 mg, 0.50 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (14 mg,0.073 mmol). The mixture in a sealed tube was heated at 130° C.overnight. After being cooled down to room temperature, H₂O (5 mL) wasadded to induce precipitation, which was collected and dried on vacuumto give a solid (38 mg).

To a solution of the solid (38 mg, 0.080 mmol) in DMF (3 mL), a solutionof oxone (145 mg, 0.47 mmol) in H₂O (2 mL) was added. The mixture wasstirred at room temperature overnight. It was then purified by HPLC togive both the sulfone (5 mg) and sulfoxide (4 mg) products. MS 507.0 and509.0 (M+H, Cl pattern, for sulfone); 491.0 and 493.0 (M+H, Cl pattern,for sulfoxide).

Example 535-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfinyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(66) and5-chloro-N-((1-(4-(3-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-2-(methylsulfonyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(67)

A mixture of5-chloro-N-((1-(4-iodophenyl)-2-(methylthio)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(50 mg, 0.10 mmol), 3-fluoro-2-hydroxypyridine (30 mg, 0.26 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (70 mg, 0.50 mmol) inDMSO (2 mL) was degassed with Ar before being charged with CuI (28 mg,0.15 mmol). The mixture in a sealed tube was heated at 130° C.overnight. After being cooled down to room temperature, H₂O (5 mL) wasadded to induce precipitation, which was collected and dried on vacuumto give a solid (34 mg).

To a solution of the solid (34 mg, 0.072 mmol) in DMF (4 mL), a solutionof oxone (200 mg, 0.65 mmol) in H₂O (3 mL) was added. The mixture wasstirred at room temperature overnight. It was then purified by HPLC togive both the sulfone (2 mg) and sulfoxide (4 mg) products. MS 507.0 and509.0 (M+H, Cl pattern, for sulfone); 491.0 and 493.0 (M+H, Cl pattern,for sulfoxide).

Example 545-chloro-N-((1-(4-(5-fluoro-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(68)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide1-6 (66 mg, 0.15 mmol), 5-fluoro-2-hydroxypyridine (46 mg, 0.40 mmol),8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg,0.079 mmol). The mixture in a sealed tube was heated at 130° C.overnight. The mixture was then purified by HPLC to give the titledcompound (6 mg). MS 429.0 and 431.0 (M+H, Cl pattern).

The compounds in the following Table 1 may be prepared using methodssimilar to those above.

TABLE 1 No. Structure Name 69

5-chloro-N-((1-(2-(2- methoxyethoxy)-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 70

(R)-5-chloro-N-((1-(2-(2,3- dihydroxypropoxy)-4-(2- oxopyridin-1(2H)-yl)phenyl-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 71

(S)-5-chloro-N-((1-(2-(2,3- dihydroxypropoxy)-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 72

5-chloro-N-((1-(2-(2- hydroxypyridin-4-yl)-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 73

5-chloro-N-((1-(2-(6- hydroxypyridin-3-yl)-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 74

N-((1-(2-(6-aminopyridin-3- yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)-5- chlorothiophene-2- carboxamide75

5-chloro-N-((1-(4-(4-fluoro- 2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 76

5-chloro-N-((1-(4-(6-fluoro- 2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 77

5-chloro-N-((1-(4-(5- hydroxy-2-oxopyridin- 1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide 78

5-chloro-N-((1-(4-(6- hydroxy-2-oxopyridin- 1(2H)-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2- carboxamide

Example 55

This example illustrates methods for evaluating the compounds of theinvention, along with results obtained for such assays. The in vitro andin vivo human Factor Xa activities of the inventive compounds can bedetermined by various procedures known in the art, such as a test fortheir ability to inhibit the activity of human plasma Factor Xa. Thepotent affinities for human Factor Xa inhibition exhibited by theinventive compounds can be measured by an IC₅₀ value (in nM). The IC₅₀value is the concentration (in nM) of the compound required to provide50% inhibition of human Factor Xa proteolytic activity. The smaller theIC₅₀ value, the more active (potent) is a compound for inhibiting FactorXa activity.

An in vitro assay for detecting and measuring inhibition activityagainst Factor Xa is as follows:

IC₅₀ and Ki Determinations:

Substrate:

The substrate S-2765 (Z-D-Arg-Gly-Arg-pNA.HCl) was obtained fromDiapharma (West Chester, Ohio).

Enzyme:

The human plasma protein factor Xa was purchased from HaematologicTechnologies (Essex Junction, Va.).

Methods:

IC₅₀ Determinations

All assays, which are performed in 96-well microtiter plates, measureproteolytic activity of the enzyme (factor Xa) by following cleavage ofa paranitroanilide peptide substrate. The assay buffer used forproteolytic assays was Tris buffered saline (20 mM Tris, 150 mM NaCl, 5mM CaCl₂, 0.1% Bovine serum albumin (BSA), 5% Dimethly Sulfoxide (DMSO)pH 7.4). In a 96-well microtiter plate, inhibitor was serially dilutedto give a range of final concentrations from 0.01 nM to 10 μM. Duplicatesets of wells were assayed and control wells without inhibitor wereincluded. Enzyme was added to each well, (factor Xa concentration=1 nM),the plate was shaken for 5 seconds and then incubated for 5 minutes atroom temperature. S2765 was added (100 μM final) and the plate wasshaken for 5 seconds (final volume in each well was 200 μl). The degreeof substrate hydrolysis was measured at 405 nm on a Thermomax platereader (Molecular Devices, Sunnyvale, Calif.) for 2 minutes. The initialvelocities of substrate cleavage (mOD/min), for each range of inhibitorconcentrations, were fitted to a four parameter equation using Softmaxdata analysis software. The parameter C, derived from the resultingcurve-fit, corresponded to the concentration for half maximal inhibition(IC₅₀).

K_(i) Determination

The assay buffer for this series of assays was Hepes buffered saline (20mM Hepes, 150 mM NaCl, 5 mM CaCl₂, 0.1% PEG-8000, pH 7.4). In a 96-wellmicrotiter plate, inhibitor was serially diluted in a duplicate set ofwells to give a range of final concentrations from 5 pM to 3 μM.Controls without inhibitor (8 wells) were included. The enzyme, factorXa (final concentration=1 nM) was added to the wells. The substrateS-2765 (final concentration=200 μM) was added and the degree ofsubstrate hydrolysis was measured at 405 nm on a Thermomax plate readerfor 5 minutes, using Softmax software. Initial velocities (mOD/min) wereanalyzed by non-linear least squares regression in the Plate K_(i)software (BioKin Ltd, Pullman, Wash.) [Kusmic, et al., AnalyticalBiochemistry 281: 62-67, 2000]. The model used for fitting the inhibitordose-response curves was the Morrison equation. An apparent K_(i) (Ki*)was determined. The overall K_(i) was calculated using the followingequation:

${Ki} = \frac{{Ki}^{*}}{1 + \frac{\lbrack S\rbrack}{Km}}$where [S] is substrate concentration (200 μM) and K_(m), the Michaelisconstant for S2765.

The following examples exhibited Factor Xa IC₅₀ values less than orequal to 100 nM: 10-12, 14, 15, 18, 21-27, 30, 32, 33-36, 39-45, 47-53,55-59, 61-62, and 64-67.

The following examples exhibited Factor Xa IC₅₀ values greater than 100nM and less than 500 nM: 17, 19, 28, and 46.

The following examples exhibited Factor Xa IC₅₀ values greater than orequal to 500 nM: 13, 16, 20, 29, 31, 37-38, 54, 60, and 63.

Example 56

Compound 10 was used in the rat investigation. An intravenous (IV) andoral (PO) dose of Compound 10 (1.0 and 10 mg/kg, respectively) wasprepared. The IV dose was solubilized in 50% PEG300 to yield a finalconcentration of 1.0 mg/mL with a final pH of 5.13. The PO dose wassuspended in 0.5% methylcellulose at a concentration of 2.0 mg/mL with afinal pH of 2.70.

For the dog and monkey study, Compound 10 was also used. An IV and POdose of Compound 10 (1.0 and 5.0 mg/kg, respectively) was prepared. TheIV dose was formulated similarly to that used in the rat study (50%PEG300 in water). The PO dose was suspended in 0.5% methylcellulose at aconcentration of 1.0 mg/mL with a final pH of approximately 3.50.

Study Design

A total of six male Sprague-Dawley rats (n=3/dosing group) from CharlesRiver Laboratories (Hollister, Calif.), three male beagle dogs fromMarshall BioResources (North Rose, N.Y.) and three male rhesus monkeyswere utilized. All surgical procedures in rat (femoral and jugular veincatheterizations) were performed 8 days prior to utilization in thestudy and rats were acclimated in-house 5 days prior to utilization.Dogs were acclimated in-house at least seven days prior to utilizationand were returned to the colony at the completion of the study. Monkeystudies were conducted by an off-site contract laboratory.

All animals were fasted from the afternoon prior to study initiation totwo hours post-dose (approximately 18 hours). Water was provided adlibitum. All animal rooms were on a 12 hour light-dark cycles (6 A.M. to6 P.M.). On the morning of experimentation, animals were weighed. Ratfemoral and jugular (IV only) vein blood lines were exteriorized andattached to access ports. Dogs were weighed and shaved at blood samplingand IV dosing sites (along both cephalic and saphenous veins).

All animals were dosed based on individual weights with a PO gavagevolume of 5.0 mL/kg and an IV bolus dose volume of 1.0 mL/kg. Bloodsamples were obtained on 3.8% TSC (1:10 dilution) over a 24, 56, and 96hour period post-dosing for the rat, dog, and monkey, respectively.Blood samples were centrifuged for platelet poor plasma, and resultingplasma was stored at −20° C. until sample analysis. Rat urine sampleswere collected on 200 μL of 2% boric acid from animals in the IV groupat 0 (overnight), 10, and 24 hours post-dose. At collection times, urinevolume and water consumption was recorded. Urine samples were stored at−20° C. until sample analysis.

Sample Analysis

Plasma and urine samples were analyzed for Compound 10 concentrationusing a liquid chromatography tandem mass spectrometry (LC/MS/MS). Inbrief, plasma and urine samples were processed in a 96-well Captiva™filter plate (0.2 μm, Varian, Inc., Palo Alto, Calif.). Aliquots ofplasma samples were precipitated with acetonitrile containing 500 ng/mLofN-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamide,an internal standard. Aliquots of urine samples were diluted with plasmabefore mixing with acetonitrile containing internal standard. Themixture was vortexed and refrigerated at 4° C. for 30 minutes to allowcomplete protein precipitation. The mixture was filtered into a 96-wellcollection plate. The filtrate was injected onto a Sciex API3000LC/MS/MS equipped with a turbo-ion spray source. Compound 10 andN-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamidewere separated on a Thermo Hypersil-Keystone Betasil C₁₈ column (4.6×100mm, 5 μm; Fisher Scientific, Houston, Tex.). A mobile phase gradientmixture of 90% mobile phase A (0.5% formic acid in water) and 10% mobilephase B (0.5% formic acid in 90% acetonitrile) to 40% mobile phase B(programmed over 2.8 minutes). The peak areas of the m/z 411→250 production (Compound 10) were measured against those of the m/z 470→342 production(N-(2-(5-chloropyridin-2-ylcarbaomoyl)-4-methoxyphenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamide)in positive ion mode. The analytical range was 0.500 to 10,000 ng/mL.

Data Analysis

Sample Compound 10 concentrations below the lower limit of quantitation(LLQ) were reported as <0.500 ng/mL. These values were treated as zerofor pharmacokinetic calculations.

Compound 10 pharmacokinetic parameter values were calculated bynoncompartmental analysis of the plasma concentration-time data usingWatson LIMS software (version 7.1). Terminal elimination rate constant(k) was calculated as the absolute value of the slope of linearregression of the natural logarithm (ln) of plasma concentration versustime during the terminal phase of the plasma concentration-time profile.Apparent terminal half-life (T_(1/2)) values were calculated as ln(2)/k.Area under the plasma concentration-time profile (AUC) values wereestimated using the linear trapezoidal rule. AUC_(all) values werecalculated from time 0 to the time of the last detectable concentration.AUC_((0−inf)) values were calculated as the sum of the correspondingAUC_(all) and the last detectable concentration divided by k. Systemicclearance (CL) was calculated from IV Dose/AUC_((0−inf)). Volume ofdistribution (Vz) was calculated from IV Dose/[k·AUC_((0−inf))]. Volumeof distribution at steady-state (Vss) was calculated from CL*MeanResidence Time. Maximum plasma concentrations (C_(max)) and time toreach C_(max) (T_(max)) were recorded as observed. Percentage oralbioavailability was calculated by taking the ratio of dose-normalizedAUC_((0-inf)) values (AUC/D) following PO and IV administration. Theresults are shown in Tables 2-3 and the Figures below.

TABLE 2 Pharmacokinetic parameters of Compound 10 in rat, dog, andmonkey after intravenous administration determined by noncompartmentalanalysis Mean ± SD Parameter Unit Rat Dog Monkey Dose mg/kg 1 1 1T_(1/2) hr 2.86 ± 1.40 AUC_(all) ng * hr/ 5376 ± 1186 1615 ± 360 12550 ±5995  mL AUC_((0-inf)) ng * hr/ 5404 ± 1163 1622 ± 363 12560 ± 5998  mLVz L/kg 0.757 ± 0.328 2.73 ± 2.45 2.31 ± 1.71 CL mL/min/  3.19 ± 0.73410.7 ± 2.69 1.66 ± 1.06 kg Vss L/kg 0.368 ± 0.026 0.843 ± 0.288 0.353 ±0.059 Dose % 0.248 ± 0.019 excreted unchanged in urine Noncompartmentalanalysis was performed using Watson LIMS software (version 7.1).T_(1/2): Terminal half-life AUC: Area under the plasma concentration vs.time curve Vz: Volume of distribution CL: Systemic clearance Vss: Volumeof distribution at steady-state

TABLE 3 Pharmacokinetic parameters of Compound 10 in rat, dog, andmonkey after oral administration determined by noncompartmental analysisMean ± SD Parameter Unit Rat Dog Monkey Dose mg/kg 10 5 5 T_(1/2) hr2.72 ± 0.29 T_(max) hr 0.250 ± 0.00  0.583 ± 0.382 2.00 ± 0.00 C_(max)ng/mL 28890 ± 2084  2717 ± 474  6041 ± 1877 AUC_(all) ng * hr/ 68510 ±12510 5464 ± 1471 42140 ± 17240 mL AUC_((0-inf)) ng * hr/ 68590 ± 124905475 ± 1475 42150 ± 17250 mL AUC/D kg * hr/ 6859 ± 1249 1095 ± 295  8430± 3449 mL F %  127 ± 23.1 68.5 ± 15.5 71.6 ± 18.1 Noncompartmentalanalysis was performed using Watson LIMS software (version 7.1).T_(1/2): Terminal half-life T_(max): Time to reach maximal plasmaconcentration C_(max): Maximal plasma concentration AUC: Area under theplasma concentration vs. time curve % F: Absolute bioavailability

The present invention provides a number of embodiments. It is apparentthat the examples may be altered to provide other embodiments of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments, which have been represented by way of example.

1. A compound having the following formula:

wherein R¹ is selected from the group consisting of halogen, C₁₋₈ alkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl; R² and R³ are independently selected fromthe group consisting of hydrogen, halogen, C₁₋₄ alkyl,SR^(4a),S(O)R^(4a), and S(O)₂R^(4a) R⁴ is selected from the groupconsisting of halogen, OR^(4a), SR^(4a), S(O)R^(4a), S(O)₂R^(4a),NR^(4a)R^(4b), CO₂R^(4a),

wherein each of these ring systems is optionally substituted with from 1to 3 substituents independently selected from the group consisting ofhalogen, amino, oxo, C₁₋₈ alkyl, C₁₋₈ haloalkyl, hydroxy, C₁₋₈ alkoxy,heterocycloalkyl, heteroaryl and heteroaryl-C₁₋₄ alkyl; each R^(4a) orR^(4b) is independently hydrogen or C₁₋₄ alkyl, optionally substitutedwith from 1 to 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, alkoxy, heterocyclyl, oxo, amino andcarboxyl; R⁶ is selected from the group consisting of hydrogen, halogen,and C₁₋₄ alkyl; the subscript n is an integer from 0 to 2; the wavy lineindicates the point of attachment to the rest of the molecule; or apharmaceutically acceptable ester or salt thereof.
 2. The compound ofclaim 1, wherein R¹ is halogen.
 3. The compound of claim 1, having theformula selected from the group consisting of

or a pharmaceutically acceptable salt or ester thereof.
 4. A compositioncomprising a pharmaceutically acceptable excipient and a compound ofclaim
 1. 5. A method for preventing or treating thrombosis in a mammalcomprising administering to said mammal a therapeutically effectiveamount of a compound of claim
 1. 6. The method in accordance with claim5, wherein the thrombosis is associated with a condition selected fromthe group consisting of acute coronary syndrome, myocardial infarction,unstable angina, refractory angina, occlusive coronary thrombusoccurring post-thrombolytic therapy or post-coronary angioplasty, athrombotically mediated cerebrovascular syndrome, embolic stroke,thrombotic stroke, transient ischemic attacks, venous thrombosis, deepvenous thrombosis, pulmonary embolus, coagulopathy, disseminatedintravascular coagulation, thrombotic thrombocytopenic purpura,thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation such as cardiac or other intravascularcatheterization, intra-aortic balloon pump, coronary stent or cardiacvalve, and conditions requiring the fitting of prosthetic devices.
 7. Amethod for inhibiting coagulation of a blood sample comprising saidsample with a compound of claim
 2. 8. The method of claim 6, wherein thecondition is selected from the group consisting of embolic stroke,thrombotic stroke, venous thrombosis, deep venous thrombosis, acutecoronary syndrome, and myocardial infarction.